First synthesis of acylated nitrocyclopropanes

Introduction

3-Arylated 2-nitrocyclopropane-1,1-dicarbonylic acid esters 1a have recently attracted considerable attention from synthetic organic chemists. In addition to their polyfunctionality, their ring strain and electron deficiency lead to a wide variety of reactivities. Based on their electron-deficient nature, these compounds have been used as substrates in the reaction with dinucleophiles such as 2-aminopyridines, which affords pyrido[1,2-a]pyrimidinones through ring opening (Scheme 1, reaction a) [1]. Chemical transformations that take advantage of polyfunctionality are also possible. A six-membered ring forms between the aryl group and ester functionality through an intramolecular aza-Wittig reaction, yielding cyclopropane-fused 2-quinolones [2]. A nitro group not only activates substrates and stabilizes the α-anion as an electron-withdrawing group but also acts as a nucleophile, electrophile, and leaving group, exhibiting diverse reactivities [3]. For example, when esters 1a are subjected to Lewis acid-induced denitration, highly electron-deficient enones (reaction b) [4] are obtained. The latter compounds are highly reactive and undergo reaction with, e.g., mercaptoacetaldehyde affording thiophenes (reaction c) [5] or with activated (hetero)aromatic compounds to give diarylated (oxoalkyl)malonates [6]. In the reaction using tin(II) chloride as the Lewis acid, the ring opening and nucleophilic attack of the nitro group occur, to produce functionalized isoxazolines (reaction d) [7]. In contrast, denitration under basic conditions generates highly reactive allenes (reaction e), which serve as synthetic intermediates for polyfunctionalized enynes [8]. The ring strain of the cyclopropane ring facilitates the cleavage of the C–C bond, and both cation and anion are stabilized by the adjacent phenyl group and ester functions, respectively (reaction f). These structural features enable the construction of a five-membered ring upon treatment with alkenes [9], diazo compounds (reaction g) [10], and nitriles [11].

Several approaches are available for the synthesis of cyclopropanedicarboxylates 1a, which consist of three steps: 1) conjugate addition, 2) halogenation, and 3) ring closure (Scheme 2). β-Nitrostyrene 2 serves as an appropriate acceptor for conjugate addition by diethyl malonate (3a) to afford adduct 4a, in which the methine group flanked by two carbonyl groups is readily halogenated, and the subsequent intramolecular nucleophilic substitution by nitronic acid furnishes cyclopropane 1a (method a) [1,4,12,13]. Halogenated malonate 6a [7,14-17] and nitrostyrene 7 [18] can also be used as substrates in this protocol (methods b and c, respectively). In these methods, diesters are mostly used as 1,3-dicarbonyl compounds, with acetylacetone 3b used in only three cases [12,13,19], to the best of our knowledge. Extending beyond Scheme 2, only two syntheses of nitrocyclopropanes containing cyclic keto esters or diketones have been reported [20,21]. These findings indicate that the synthesis of nitrocyclopropanes with an acyl group is quite difficult, although they would be very useful in synthetic chemistry, if available. In this study, we investigated the synthesis of nitrocyclopropanes using keto esters 3c–f and diketones 3b and 3g instead of diester 3a as the starting 1,3-dicarbonyl compounds.

Results and Discussion

We commenced our study using ethyl acetoacetate (3c) as starting 1,3-dicarbonyl compound according to method b (Scheme 2). After heating an acetonitrile solution of 3c, N-bromosuccinimide, and p-toluenesulfonic acid [7], α-bromoacetoacetate 6c was isolated with a 44% yield after purification of the reaction mixture by silica gel column chromatography (Scheme 3). In the subsequent reaction of the α-brominated product 6c with nitrostyrene 2a in the presence of triethylamine, the complete consumption of 2a was confirmed, however, the reaction mixture was complicated, and the desired cyclopropane 1c was not detected (Scheme 3).

Next, method a (Scheme 2) was employed to synthesize nitrocyclopropanes 1 possessing an acyl group. Keto esters 3c–f and diketones 3b and 3g underwent conjugate addition to nitrostyrene 2a to afford the corresponding adducts 4b–g with moderate yields (Table 1). For unsymmetrical substrates, almost equal amounts of diastereomers were formed. Whereas 4b was isolated by recrystallization of the reaction mixture from ethanol, the other adducts 4c–g were easily isolated by column chromatography.

For comparison with previously reported results, adduct 4b, derived from acetylacetone (3b), was subjected to cyclopropanation according to a method described in the literature [13]. To a solution of adduct 4b in toluene, (diacetoxyiodo)benzene and tetrabutylammonium iodide were added, and the resulting mixture was stirred at room temperature for 14 h. Unexpectedly, from the reaction mixture, compound 8b was isolated after column chromatography with 21% yield instead of the desired cyclopropane 1b (Scheme 4).

The NMR data for the ring protons of product 8b and compound 1b’ are listed in Table 2. Although the benzene ring in compound 8b is methyl-substituted, a ¹H NMR spectrum similar to those in the literature was observed [12,13,19], indicating that both compounds have the same framework. Surprisingly, the coupling constants were considerably smaller than those of 1a (Ar = MeC₆H₄), and the same tendency was previously found in the literature [12,13]. However, a reasonable explanation was not given for the different coupling constants between diester 1a and diketone 1b’. In the ¹³C NMR spectrum of diester 1a, two separate signals of carbonyl groups were observed at 163.2 and 163.3 ppm, indicating that the two ester functionalities were not equivalent. Moreover, the spectrum of compound 8b revealed only a single signal of a carbonyl carbon at 193.2 ppm, and a signal of a quaternary carbon at 167.0 ppm, which could not be assigned. These spectral data prompted us to reconsider the structure of compound 8b.

The reaction of chlorinated nitrostyrene 2b with acetylacetone (3b) was in the same way, and the obtained product 9 was converted to the 2,4-dinitrophenylhydrazone 10 to facilitate the crystallization for X-ray crystallography, which showed that a 2,3-dihydrofuran framework had formed (Scheme 4, bottom). Hence, we clarified that product 8b was not the desired cyclopropane, but a dihydrofuran, so the cyclopropane 1b’ reported in the literature [12,13,19] is presumably incorrect [22]. In the cases of donor–acceptor cyclopropanes possessing an electron-donating group such as an alkoxy or amino group, ring expansion caused by an intramolecular attack of nitro oxygen occurs, leading to five-membered cyclic nitronates [23]. To the contrary, such reaction was not observed at all, which is presumably due to the lower electron-donating ability of the benzene ring.

The other adducts 4c–g were subjected to the cyclization under the same conditions (Table 3). When the adduct of ethyl acetoacetate (4c) was used, dihydrofuran 8c was obtained as the main product, with small amounts of cyclopropane 1c (Table 3, entry 1).

With a bulkier acyl group the yield of 1 was higher, and the yield increased up to 56% in the reaction using adduct 4f, which was derived from ethyl benzoylacetate (3f) (Table 3, entries 1–4). The yield of aromatized furans 8 also increased with an increase in the bulkiness of the acyl group. A similar tendency was observed when adducts 4b and 4g derived from diketones 3b and 3g were reacted in the same way (Table 3, entries 5 and 6).

To obtain insight into the two cyclization modes, the reaction of 4e was monitored by ¹H NMR in 5 min intervals (Figure 1). In Figure 1, the red triangles are the total yields of furans 8e and 11e. The yields of cyclopropane 1e and furans 8e and 11e increased with increasing reaction time, without disturbing the shape of the graph. In addition, we confirmed that isolated cyclopropane 1e did not change upon treatment with (diacetoxyiodo)benzene and tetrabutylammonium iodide. These findings indicate that no equilibrium existed between cyclopropane 1e and dihydrofuran 8e, and that these products were competitively formed.

A plausible mechanism explaining the experimental results is illustrated in Scheme 5. In this reaction, acetoxyiodine serves as the active species [13,24]. Nitronic acid, one of the tautomers of 4, attacks the acetoxyiodine to afford α-iododerivative 12. After the carbonyl moiety tautomerized to the enol form, a C-attack (path a) furnishes cyclopropane 1, and an O-attack (path b) furnishes dihydrofuran 8. When the R¹ group becomes bulkier, the hydroxy group may be far from the reaction site because of the steric repulsion in the stable conformation. Another possibility is that the bulky substituent may prevent the attack of other reagents and suppress the decomposition of the nitrocyclopropane framework.

The chemical transformation of cyclopropane 1e was investigated. When a solution of 1e and tin(II) chloride in benzene was heated at 100 °C for 14 h, successive ring-opening/ring-closure proceeded, to produce furan 13 with a 46% yield (Scheme 6). The coordination of two carbonyl groups to the tin species facilitated the ring opening of the cyclopropane ring to afford betaine [7], then the oxygen atom of the enolate attacked the benzyl cation to construct a five-membered ring. The subsequent elimination of nitrous acid, accompanied by aromatization, yielded furan 13. In addition to the stepwise mechanism, a concerted ring-expansion can be also acceptable [25].

Conclusion

Although nitrocyclopropanedicarboxylic acid esters 1a have been used in organic syntheses, nitrocyclopropanes possessing an acyl group are unknown, except for a derivative of cyclic diketone [20,21]. Although diacetyl derivative 13 has been reported in some studies [12,13,19], we corrected its structure to dihydrofuran 8. This is the first report of the synthesis of acylated nitrocyclopropanes 1. After the conjugate addition of the 1,3-dicarbonyl compound 3 to nitrostyrene 2 and the α-iodination of the adduct 4, two cyclization modes became possible owing to the ambident property of enol 12. Dihydrofuran 8 was formed in the case of an O-attack, and nitrocyclopropane 1 was formed in the case of a C-attack. Furthermore, the latter cyclization predominantly proceeded as the acyl group became bulkier. The polyfunctionality of products 1 and 8 facilitate further chemical conversion [22]. Nitrocyclopropane 1e was converted into furan 13 by treatment with tin(II) chloride. The findings obtained herein will be useful for researchers studying organic syntheses using functionalized cyclopropanes.

Experimental

General

All reagents were purchased from commercial sources and used without further purification. ¹H and¹³C NMR spectra were recorded on Bruker DPX-400 and JEOL JMN-ECZ400S spectrometers (400 MHz and 100 MHz, respectively) in CDCl₃ using TMS as an internal standard. The assignments of the ¹³C NMR signals were performed by DEPT experiments. IR spectra were recorded on a JASCO FT/IR-4200 spectrometer equipped with an ATR detector. High-resolution mass spectra were obtained on AB SCIEX Triplet TOF 4600 and Bruker Compact mass spectrometers. All measurements were made on a Rigaku AFC7R diffractometer with graphite monochromatized Mo Kα radiation. Melting points were recorded on an SRS-Optimelt automated melting point system and were uncorrected.

Preparation of nitrostyrenes 2

Nitrostyrenes 2 were prepared according to the literature [26]. To a solution of ammonium acetate (2.63 g, 36 mmol) in acetic acid (10 mL), were added 4-methylbenzaldehyde (2 mL, 15 mmol) and nitromethane (5.3 mL, 98 mmol), and the resultant mixture was heated at 100 °C for 6 h. After adjusting the pH value to 7 by 2 M sodium hydroxide (40 mL, 80 mmol), the mixture was extracted with ethyl acetate (30 mL × 3), and the organic layer was washed with brine (30 mL × 1), dried over magnesium sulfate, and concentrated to afford nitrostyrene 2a (17.4 g, 71%, mp 56–58 °C) as a yellow solid. Nitrostyrene 2b (mp 112–114 °C) was prepared in the same way. The structure was confirmed by comparison with those reported in the literature [26].

Conjugate addition of 1,3-dicarbonyl compound 3 to nitrostyrene 2

Adduct 4 was prepared according to the literature [27]. To a solution of nitrostyrene 2a (978 mg, 6 mmol) in dichloromethane (8 mL), were added ethyl benzoylacetate (3f, 1.04 mL, 6 mmol) and triethylamine (84 μL, 0.6 mmol), and the resultant solution was stirred at room temperature for 14 h. After removal of the solvent under reduced pressure, the residual pale-yellow solid was extracted with hot hexane (20 mL × 4). The hexane was concentrated, and the residual yellow oil was subjected to column chromatography on silica gel to afford ethyl 2-benzoyl-3-(4-methylphenyl)-4-nitrobutanoate (4f) [28] (eluted with hexane/ethyl acetate 95:5, 1.43 g, 4.02 mmol, 67%) as a pale-yellow oil. Major isomer ¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J = 7.2 Hz, 3H), 4.17 (q, J = 1.8, 7.2 Hz, 2H), 4.48–4.37 (m, 1H), 4.81–4.72 (m, 1H), 4.97–4.88 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 7.6, 7.2 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.6 (CH₃), 21.1 (CH₃), 42.8 (CH), 57.1 (CH), 61.9 (CH₂), 78.1 (CH₂), 128.1 (CH), 128.6 (CH), 128.9 (CH), 128.9 (CH), 133.8 (C), 134.2 (CH), 135.9 (C), 138.0 (C), 167.8 (C), 192.9 (C). Minor isomer ¹H NMR (400 MHz, CDCl₃) δ 1.17 (dd, J = 7.2, 7.2 Hz, 3H), 3.88 (dq, J = 7.2 Hz, 1H), 3.88 (dq, J = 7.2 Hz, 1H), 4.48–4.37 (m, 1H), 4.81–4.72 (m, 1H), 4.97–4.88 (m, 2H), 7.02 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 7.41 (dd, J = 7.6, 7.2 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9 (CH₃), 21.0 (CH₃), 42.8 (CH), 56.5 (CH), 62.2 (CH₂), 78.1 (CH₂), 127.8 (CH), 128.7 (CH), 129.6 (CH), 129.6 (CH), 133.2 (C), 133.8 (CH), 135.1 (C), 137.8 (C), 167.0 (C), 192.7 (C).

Although the adduct was obtained as a mixture of diastereomeric isomers (54:46), these isomers were subjected to subsequent cyclization without separation. When other 1,3-dicarbonyl compounds 3 or nitrostyrene 2b were used, the reaction was conducted in the same way.

Cyclization of adduct 4

Cyclization was conducted according to the literature [13]. To a solution of adduct 4f (593 mg, 1.67 mmol) in toluene (7 mL), were added (diacetoxyiodo)benzene (539 mg, 2.5 mmol) and tetrabutylammonium iodide (618 mg, 2.5 mmol), and the resultant mixture was stirred at room temperature for 14 h. The solution was subjected to column chromatography on silica gel to afford ethyl 4,5-dihydro-4-(4-methylphenyl)-5-nitro-2-phenylfuran-3-carboxylate (8f) (eluted with hexane/ethyl acetate 95:5, 53 mg, 0.15 mmol, 9%) as a pale-yellow oil, ethyl 1-benzoyl-2-(4-methylphenyl)-3-nitrocyclopropanecarboxylate (1f) (eluted with hexane/ethyl acetate 90:10, 330 mg, 0.94 mmol, 56%) as a yellow oil, and ethyl 4-(4-methylphenyl)-5-nitro-2-phenylfuran-3-carboxylate (11f) (eluted with hexane/ethyl acetate 90:10, 100 mg, 0.28 mmol, 17%) as a yellow oil, respectively.

Ethyl 1-benzoyl-2-(4-methylphenyl)-3-nitrocyclopropanecarboxylate (1f): Major isomer: ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.1 Hz, 3H), 2.34 (s, 3H), 3.90 (q, J = 7.1 Hz, 2H), 4.34 (d, J = 5.8 Hz, 1H), 5.73 (d, J = 5.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.48 (dd, J = 7.5, 7.8 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5 (CH₃), 21.1 (CH₃), 36.5 (CH), 49.8 (C), 62.7 (CH₂), 67.8 (CH), 127.5 (C), 128.2 (CH), 128.3 (CH), 129.1 (CH), 129.5 (CH), 134.1 (CH), 135.1 (C), 138.3 (C), 164.3 (C), 186.6 (C); IR (ATR): 1362, 1557, 1682, 1695 cm⁻¹; HRESIMS–TOF (m/z): [M + H]⁺ calcd for C₂₀H₁₉NO₅, 354.1336; found, 354.1328. Minor isomer: ¹H NMR (400 MHz, CDCl₃) δ 0.99 (t, J = 7.1 Hz, 3H), 2.20 (s, 3H), 4.11 (q, J = 7.1 Hz, 2H), 4.44 (d, J = 6.2 Hz, 1H), 5.73–5.72 (overlapped, 1H), 7.00 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 7.7, 7.8 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5 (CH₃), 21.0 (CH₃), 38.8 (CH), 52.4 (C), 63.1 (CH₂), 66.2 (CH), 126.9 (C), 127.6 (CH), 128.6 (CH), 128.6 (CH), 129.5 (CH), 133.8 (CH), 135.6 (C), 138.4 (C), 164.8 (C), 187.8 (C).

Ethyl 4,5-dihydro-4-(4-methylphenyl)-5-nitro-2-phenylfuran-3-carboxylate (8f): ¹H NMR (400 MHz, CDCl₃) δ 1.08 (dd, J = 7.2, 7.2 Hz, 3H), 4.02 (dq, J = 7.2, 10.8 Hz, 1H), 4.06 (dq, J = 7.2, 10.8 Hz, 1H), 4.80 (d, J = 1.7 Hz, 1H), 5.86 (d, J = 1.7 Hz, 1H), 7.21–7.20 (br s, 4H), 7.54–7.46 (m, 3H), 8.09–8.07 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9 (CH₃), 21.1 (CH₃), 57.0 (CH), 60.6 (CH₂), 107.7 (C), 108.9 (CH), 127.0 (CH), 127.7 (C), 128.0 (CH), 129.9 (CH), 130.0 (CH), 134.9 (C), 138.3 (C), 162.7 (C), 163.5 (C); IR (ATR): 1371, 1572, 1697 cm⁻¹; HRESIMS–TOF (m/z): [M + H]⁺ calcd for C₁₄H₁₅NO₄, 354.1336; found, 354.1324.

Ethyl 4-(4-methylphenyl)-5-nitro-2-phenylfuran-3-carboxylate (11f): ¹H NMR (400 MHz, CDCl₃) δ 0.99 (t, J = 7.2 Hz, 3H), 2.42 (s, 3H), 4.12 (q, J = 7.2 Hz, 2H), 7.26 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H), 7.52–7.47 (m, 3H), 7.93 (dd, J = 7.2, 1.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5 (CH₃), 21.4 (CH₃), 61.6 (CH₂), 118.2 (C), 125.6 (C), 127.3 (C), 128.4 (CH), 128.7 (CH), 128.9 (CH), 129.2 (CH), 131.2 (CH), 139.3 (C), 154.9 (C), 162.5 (C), Two signals were lacked presumably due to overlapping. IR (ATR): 1359, 1593, 1730 cm⁻¹; HRESIMS–TOF (m/z): [M + Na]⁺ calcd for C₁₉H₁₉NO₆, 374.0999; found, 374.1000.