1,3-Dipolar cycloaddition of nitrones to carbon–carbon multiple bonds is a widely used method of constructing the isoxazolidine ring [1, 2]. These compounds attract special attention owing to their potential biological activity, and also the possibility of using them to obtain amino alcohols, which are precursors of such natural compounds as β-lactams and alkaloids [3]. Unlike acyclic unsaturated compounds, the methylene-cyclopropanes, as a result of significant strain energy, fairly readily entered into cycloaddition reactions with nitrones. As a result, mixtures of 4- and 5-spirocyclopropaneisoxazolidines were formed, the proportions of which depended on substituents both in the nitrone and in the methylenecyclopropane [4].

We have shown previously that on interacting C,N-diaryl- and N-aryl-C-carbamoylnitrones with esters of methylenecyclopropanedicarboxylic acids only 4-spirocyclopropaneisoxazolidines were formed [5-8]. At the same time, the formation of azeto- and pyrroloquinolines, observed on interacting C,C-disubstituted nitrones with the same esters, involved 5-spirocyclopropaneisoxazolidine intermediates [9].

figure a

To expand the range of methylenecyclopropanes involved in reaction with nitrones, we have in this case studied the interaction of C-carbamoylnitrones 1a-f with 1-benzylidene-3,3-dichloro-2,2-dimethyl-cyclopropane (2). It was established that on heating the nitrones 1a-e with dichlorocyclopropane 2 in toluene for 4–5 h, only a single diastereomer of the 4-spirocyclopropaneisoxazolidines 3a-e was formed, and compounds 3a-e were isolated in yields of 58-70%. Interaction with the N-methylnitrone 1f required longer heating (25 h).

The structures of cycloadducts 3a-f were established on the basis of spectral data. In the 1H NMR spectra there were singlets for the protons of the two methine groups at 4.18-4.90 and 5.41-5.64 ppm, and a singlet for the amide NH group at 9.25-9.45 ppm. In the 13C NMR spectra of compounds 3a-f there were three signals for the quaternary carbon atoms of the cyclopropane ring at 32.2-33.4, 49.0-49.9, and 74.6-76.3 ppm, a signal for the methine carbon atom of the isoxazolidine ring, linked with nitrogen, at 74.2-74.7 ppm, and a signal for the methine carbon atom, linked with oxygen, at 84.0-84.9 ppm. In the IR spectra of compounds 3a-f there were absorption bands of the amide carbonyl groups at 1700–1688 cm-1 and of the NH groups at 3370–3340 cm-1. The elemental analysis data confirmed the composition of the obtained products.

figure b

The stereochemistry of adduct 3e was established with the aid of two-dimensional NMR spectroscopy. The main interactions between the protons found in the 1H-1H NOESY spectrum of compound 3e are shown in Fig. 1 including the cross peaks corresponding to isoxazolidine ring protons H-3 and H-5 interacting with the methyl group protons. Also observed was the interaction of the aromatic protons of the arylcarbamoyl group with the NH proton and with one of the cyclopropane ring methyl groups. At the same time, interaction of only one of the isoxazolidine ring protons with the methyl group protons would be expected for the trans isomer. It should be mentioned that in the reaction mixtures no 1H NMR signals were observed which might be ascribed to the other diastereomer.

Fig. 1
figure 1

Main proton interactions in the 1H-1H NOESY spectrum of compound 3e.

Full size image

The C-carbamoylnitrones 1a-f added to benzylidenecyclopropane 2 with analogous stereoselectivity to that observed previously on interacting the same nitrones and methylenecyclopropanes having acceptor ester groups on the three-membered ring. The cycloaddition of nitrones to the methylenecyclopropane 2 could proceed in two directions, through the transition state I leading to the observed diastereoisomer III, or through the transition state II, which would have led to the diastereomer IV. The second route was apparently less favored because of the steric repulsion between the syn-oriented chlorine atom and the aryl group, and also steric repulsion between the benzylidenecyclopropane phenyl group and the substituent R on the nitrone.

It has therefore been established that the addition of C-carbamoylnitrones to 1-benzylidene-3,3-di-chloro-2,2-dimethylcyclopropane proceeds regio- and stereoselectively with the formation of a single 4-spirocyclopropaneisoxazolidine diastereomer.

Experimental

The IR spectra were recorded on a Bruker Tensor 27 spectrophotometer. The 1H and 13C NMR spectra were recorded on a Bruker DPX-300 instrument (300 and 75 MHz, respectively) in CDCl3, using the residual solvent signals as a standard (7.26 ppm for the 1H nuclei, 77.2 ppm for the 13C nuclei). Elemental analysis was performed on a Hewlett-Packard 185B C,H,N-analyzer. Melting points were determined on a Boetius hot stage apparatus. C-Carbamoylnitrones 1a-f were obtained according to procedures in [6, 10, 11], and 1-benzylidene-3,3-dichloro-2,2-dimethylcyclopropane (2) by the procedure of [12].

Interaction of C -Carbamoylnitrones 1a-f with Methylenecyclopropane 2 (General Method). A solution of methylenecyclopropane 2 (272 mg, 1.2 mmol) and nitrone 1a-f (1.0 mmol) in anhydrous toluene (10 ml) was heated at 110°C (reaction time is given in the procedures for products 3a-f). Toluene was evaporated in vacuum, and the residue was separated on a silica gel column. Eluent was EtOAc-hexane. The solvent was evaporated and the residue recrystallized from EtOH.

7-( N -Phenylcarbamoyl)-1,1-dichloro-2,2-dimethyl-4,6-diphenyl-5-oxa-6-azaspiro[2.4]heptane (3a). Heating time was 5 h. Yield 275 mg (59%), white powder, mp 218-220°C. R f 0.43 (EtOAc-hexane, 1:7). IR spectrum (KBr), ν, cm-1 3370 (NH), 1700 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.80 (3H, s, CH3); 1.65 (3H, s, CH3); 4.90 (1H, s, 7-CH); 5.64 (1H, s, 4-CH); 7.17 (2H, t, J = 7.3, H Ar); 7.27-7.47 (11H, m, H Ar); 7.55 (2H, d, J = 8.7, H Ar); 9.34 (1H, s, NH). 13C NMR spectrum, δ, ppm: 23.0 (CH3), 25.9 (CH3); 33.4 (C-2); 49.9 (C-3); 74.6 (C-1); 74.7 (C-7); 84.8 (C-4); 116.2; 120.8; 124.3; 125.2; 129.2; 129.4; 129.5; 129.6; 129.7; 136.7; 137.6; 148.2; 167.5. Found, %: C 66.94; H 5.18; N 5.92. C26H24Cl2N2O2. Calculated, %: C 66.81; H 5.18; N 5.99.

7-[ N -(4-Tolyl)carbamoyl]-1,1-dichloro-2,2-dimethyl-4,6-diphenyl-5-oxa-6-azaspiro[2.4]heptane (3b). Heating time was 5 h. Yield 336 mg (70%), white powder, mp 217-218°C. R f 0.60 (EtOAc-hexane, 1:4). IR spectrum (KBr), ν, cm-1: 3358 (NH), 1693 (C=O). 1H NMR spectrum, δ, ppm: 0.79 (3H, s, CH3); 1.64 (3H, s, CH3); 2.35 (3H, s, CH3); 4.88 (1H, s, 7-CH); 5.63 (1H, s, 4-CH); 7.08-7.47 (14H, m, H Ar); 9.27 (1H, s, NH). 13C NMR spectrum, δ, ppm: 21.3 (CH3); 23.0 (CH3); 25.9 (CH3); 33.4 (C-2); 49.9 (C-3); 74.7 (C-1); 74.8 (C-7); 84.8 (C-4); 116.2; 120.9; 124.2; 128.8; 129.1; 129.3; 129.5; 129.7; 134.8; 135.1; 136.8; 148.3; 167.4. Found, %: C 66.98; H 5.28; N 5.95. C27H26Cl2N2O2. Calculated, %: C 67.36; H 5.44; N 5.82.

7-[ N -(4-Chlorophenyl)carbamoyl]-1,1-dichloro-2,2-dimethyl-4,6-diphenyl-5-oxa-6-azaspiro[2.4]heptane (3c). Heating time was 5 h. Yield 335 mg (67%), white powder, mp 208-210°C. R f 0.55 (EtOAc-hexane, 1:4). IR spectrum (KBr), ν, cm-1: 3359 (NH), 1699 (C=O). 1H NMR spectrum, δ, ppm: 0.80 (3H, s, CH3); 1.64 (3H, s, CH3); 4.87 (1H, s, 7-CH); 5.64 (1H, s, 4-CH); 7.12-7.52 (14H, m, H Ar); 9.34 (1H, s, NH). 13C NMR spectrum, δ, ppm: 23.0 (CH3); 25.8 (CH3); 33.5 (C-2); 49.8 (C-3); 74.7 (C-1); 74.8 (C-7); 84.8 (C-4); 116.2; 121.9; 124.4; 129.2; 129.4; 129.6; 130.2; 136.2; 136.6; 148.1; 167.6 (C=O). Found, %: C 61.97; H 4.78; N 5.85; C26H23Cl3N2O2. Calculated, %: C 62.23; H 4.62; N 5.58.

7-( N -Phenylcarbamoyl)-1,1-dichloro-2,2-dimethyl-4-phenyl-6-(4-tolyl)-5-oxa-6-azaspiro[2.4]heptane (3d). Heating time was 4 h. Yield 318 mg (66%), white powder, mp 193-194°C. R f 0.44 (EtOAc-hexane, 1:7). IR spectrum (CHCl3), ν, cm-1: 3370 (NH), 1700 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.79 (3H, s, CH3); 1.64 (3H, s, CH3); 2.39 (3H, s, CH3); 4.85 (1H, s, 7-CH); 5.63 (1H, s, 4-CH); 7.15-7.24 (5H, m, H Ar); 7.30-7.39 (5H, m, H Ar); 7.43-7.45 (2H, m, H Ar); 7.54 (2H, d, J = 8.0, H Ar); 9.36 (1H, s, NH). 13C NMR spectrum, δ, ppm: 21.2 (CH3); 23.0 (CH3); 25.9 (CH3); 33.3 (C-2); 49.8 (C-3); 74.7 (C-7); 74.8 (C-1); 84.9 (C-4); 116.1; 120.8; 125.1; 129.2; 129.4; 129.5; 129.7; 129.9; 133.7; 136.8; 137.6; 145.8; 167.6 (C=O). Found, %: C 67.49; H 5.38; N 5.87. C27H26Cl2N2O2. Calculated, %: C 67.36; H 5.44; N 5.82.

7-[ N -(4-Methoxyphenyl)carbamoyl]-1,1-dichloro-2,2-dimethyl-4-phenyl-6-(4-tolyl)-5-oxa-6-aza-spiro[2.4]heptane (3e). Heating time was 4.5 h. Yield 296 mg (58%), white powder, mp 171-172°C. R f 0.30 (EtOAc-hexane, 1:7). IR spectrum (CDCl3), ν, cm-1: 3340 (NH), 1700 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.79 (3H, s, CH3); 1.63 (3H, s, CH3); 2.38 (3H, s, CH3); 3.82 (3H, s, CH3); 4.84 (1H, s, 7-CH); 5.62 (1H, s, 4-CH); 6.89 (2H, d, J = 8.7, H Ar); 7.16 (2H, d, J = 8.7, H Ar); 7.22 (2H, d, J = 8.7, H Ar); 7.31-7.33 (3H, m, H Ar); 7.41-7.46 (4H, m, H Ar); 9.25 (1H, s, NH). 13C NMR spectrum, δ, ppm: 20.8 (CH3); 22.7 (CH3); 25.5 (CH3); 32.9 (C-2); 49.4 (C-3); 55.4 (CH3); 74.3 (C-7); 74.4 (C-1); 84.4 (C-4); 114.2; 115.7; 122.3; 128.7; 129.1; 129.3; 129.5; 130.3; 133.2; 136.5; 145.5; 156.7; 167.1 (C=O). Found, %: C 65.48; H 5.50; N 5.42. C28H28Cl2N2O3. Calculated, %: C 65.76; H 5.52; N 5.48.

7-( N -Phenylcarbamoyl)-1,1-dichloro-2,2,6-trimethyl-4-phenyl-5-oxa-6-azaspiro[2.4]heptane (3f). Heating time was 25 h. Yield 240 mg (59%), white powder, mp 116-117°C. R f 0.34 (EtOAc-hexane, 1:7). IR spectrum (CHCl3), ν, cm-1: 3342 (NH), 1703 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.78 (3H, s, CH3); 1.65 (3H, s, CH3); 2.99 (3H, s, CH3); 4.18 (1H, s, 7-CH); 5.41 (1H, s, 4-CH); 7.14 (1H, t, J = 7.3, H Ar); 7.26-7.28 (3H, m, H Ar); 7.32-7.38 (4H, m, H Ar); 7.55 (2H, d, J = 8.0, H Ar); 9.45 (1H, s, NH). 13C NMR spectrum, δ, ppm: 22.7 (CH3); 26.3 (CH3); 32.3 (C-2); 43.6 (CH3); 49.0 (C-3); 74.2 (C-7); 76.3 (C-1); 84.0 (C-4); 120.7; 124.9; 129.1; 129.3; 129.4; 129.7; 136.9; 137.8; 167.6 (C=O). Found, %: C 62.34; H 5.40; N 6.84. C21H22Cl2N2O2. Calculated, %: C 62.23; H 5.47; N 6.91.

The authors are grateful to the Russian Foundation for Basic Research for financial support (Project 12-03-01008-a).