In 1996, I. A. Aitov et al.1 described two examples of a reaction of a Kröhnke's salt 1 with (ethoxymethylidene) malononitrile (2) to form the olefin metathesis product 3. The structure of the synthesized compounds was confirmed by X-ray structural analysis; in solid state compounds 3 were in the form of Z-isomers (Scheme 1).

Scheme 1
scheme 1

ᅟ

Full size image

More recently, we have shown2 , 3 that a by-product 2-amino-1-cyanoindolizine 5a may form along with the products of the metathesis 3 in the reaction of (arylmethylidene)malononitriles 4 with Kröhnke's salt 1a possessing an ester substituent on the nitrogen atom (Scheme 2).

Scheme 2
scheme 2

ᅟ

Full size image

The reactivity of ester analogs of Kröhnke's salts 1a,b 4 , 5 with (ethoxymethylidene)malononitrile (2) has not been studied, so the aim of this work was to explore these mreactions. 2-Amino-1-cyanoindolizines 5a,b were obtained as a result of the reaction of salts 1a,b with compound 2 in low yields (23-28%). Presumably, the reaction proceeds via the intermediate 6 (Scheme 3). Indolizine 5a had previously6 been prepared by us by reacting salt 1a with malononitrile (7).

Scheme 3
scheme 3

ᅟ

Full size image

The reaction of salts 1a–d with ethyl (ethoxymethylidene)- cyanoacetate 8 afforded 1-cyanoindolizines 9a-d (Scheme 4). We assumed that decarboxylation, characteristic to enamine esters,8 occurs after the stage of formation of metathesis products 10. As a result, intermediates 11 form, cyclization of which gives indolizines 9a-d in moderate to high yields.

Scheme 4
scheme 4

ᅟ

Full size image

Characteristic to1Н NMR spectra of indolizines 9a-d is the downfield shift of the signal of the H-5 proton (9.40– 9.89 ppm) by comparison to the analogous signal in the spectra of compounds 5a,b (9.25 ppm).4 , 5 Apparently, this can be explained by an exclusive non-covalent interaction between the H-5 proton of the heterocycle with the oxygen atom of the carbonyl group. The latter is presumptively forming an intramolecular hydrogen bond with the amino group in indolizines 5a,b.

To conclude, a novel convenient method for the synthesis of 3-acyl and 3-alkoxycarbonyl-1-cyanoindolizines and their 2-amino derivatives has been developed based on the reaction of ethyl (ethoxymethylidene)- cyanoacetate or (ethoxymethylidene)malononitrile with Kröhnke's salts possessing an acyl or ester group in the substituent at the nitrogen atom.

Experimental

IR spectra were registered on an IKS-40 spectrometer in petroleum jelly (compounds 9a,b) and a Perkin Elmer Spectrum One spectrometer in KBr pellets (remaining compounds).1H and 13C NMR spectra were acquired on a Bruker Avance II-400 (400 and 100 MHz, respectively) in DMSO-d 6, with TMS as internal standard. Mass spectra were recorded on a Varian 1200 L mass spectrometer, EI ionization (70 eV) with direct sample injection. Elemental analysis was performed on a Eurovector EA-3000 Elemental analyzer. Melting points were determined on a Kofler bench. Monitoring of the reaction progress and assessment of the purity of synthesized compounds was done by TLC on Silufol UV-254 plates in acetone–hexane, 3:5 eluent system, visualization with UV or in an iodine chamber.

Synthesis of compounds 5a,b, 9a–d (General method). Nitrile 2 (0.244 g, 2.0 mmol; compounds 5a,b) or ester 8 (0.338 g, 2.0 mmol; compounds 9a–d) and Et3N (0.56 ml, 4.0 mmol) were added to a solution of 2-halopyridinium salts 1a–d (2 mmol) in EtOH (8 ml). The reaction mixture was stirred at room temperature for 4 h, then kept at 0–2°С for 24 h. The formed precipitate was filtered off, washed with MeOH (compounds 5b, 9b) or EtOH (remaining compounds), and dried.

Ethyl 2-amino-1-cyanoindolizine-3-carboxylate (5a). Yield 0.105 g (23%), colorless crystals, mp 154–155°С (EtOH) (mp 151 °С (EtOH)4).

Methyl 2-amino-1-cyanoindolizine-3-carboxylate (5b). Yield 0.121 g (28%), brown powder, mp 147–149°С (MeOH) (mp 148–150°С (MeOH)5).

Ethyl 1-cyanoindolizine-3-carboxylate (9a). Yield 0.295 g (69%), orange needles, mp 70–71°С (EtOH). IR spectrum, ν, cm–1: 1699 (С=О), 2214 (C≡N).1H NMR spectrum, δ, ppm (J, Hz): 1.37 (3H, t, J = 7.1, OСН2CH3); 4.35 (2H, q, J = 7.1, OCH2CH3); 7.21 (1H, t, J = 7.0, H-6); 7.47–7.51 (1H, m, H-7); 7.80–7.82 (2H, m, H-2,8); 9.46 (1H, d, J = 7.0, H-5). 13C NMR spectrum, δ, ppm: 14.7 (OСН2СН3); 60.9 (OСН2СН3); 83.0 (С-1); 115.2 (CN); 115.6 (C-3); 116.2; 117.6; 124.9; 127.4; 128.3; 140.4 (С-8a); 160.0 (С=О). Mass spectrum, m/z (I rel, %): 214 [M]+ (64), 187 (32), 186 (100). Found, %: С 67.31; Н 4.69; N 13.02. С12H10N2O2. Calculated, %: С 67.28; Н 4.71; N 13.08.

Methyl 1-cyanoindolizine-3-carboxylate (9b). Yield 0.132 g (33%), white powder, mp 145–146°С (MeOH). IR spectrum, ν, cm–1: 1692 (С=О), 2218 (C≡N).1H NMR spectrum, δ, ppm (J, Hz): 3.85 (3Н, s, ОСН3); 7.24 (1Н, t, J = 7.1, Н-6); 7.50–7.53 (1Н, m, Н-7); 7.83 (1Н, d, J = 8.9, Н-8); 7.95 (1Н, s, Н-2); 9.40 (1H, d, J = 7.1, H-5). 13C NMR spectrum, δ, ppm: 52.2 (СН3); 83.1 (С-1); 115.1 (CN); 115.7 (C-3); 116.3; 117.7; 125.2; 127.5; 128.4; 140.5 (С-8a); 160.5 (С=О). Mass spectrum, m/z (I rel, %): 200 [M]+ (58), 168 (56), 141 (53), 49 (100). Found, %: С 66.08; Н 4.06; N 13.95. С11H8N2O2. Calculated, %: С 66.00; Н 4.03; N 13.99.

3-Benzoylindolizine-1-carbonitrile (9c). Yield 0.482 g (98%), white powder, mp 120–122°С (EtOH). IR spectrum, ν, cm–1: 1601 (С=О), 2225 (CN). 1H NMR spectrum, δ, ppm (J, Hz): 7.33 (1Н, t, J = 7.0, Н-6); 7.55 (2Н, t, J = 7.4, Ar); 7.61–7.65 (2Н, m, H-7, H Ph); 7.75–7.80 (3Н, m, Н-2, H Ph); 7.91 (1Н, d, J = 8.9, H-8); 9.89 (1H, d, J = 7.0, H-5). 13C NMR spectrum, δ, ppm: 83.9 (С-1); 115.2 (CN); 116.6; 117.3; 122.4 (C-3); 128.6 (C Ph); 128.9; 129.0 (C Ph); 129.1; 129.4; 132.1; 138.7; 140.7 (С-8a); 184.2 (С=О). Mass spectrum, m/z (I rel, %): 246 [М]+ (100). Found, %: С 78.07; Н 4.13; N 11.45. C16H10N2O. Calculated, %: С 78.04; Н 4.09; N 11.38.

3-(4-Methoxybenzoyl)indolizine-1-carbonitrile (9d). Yield 0.353 g (64%), beige powder, mp 191–192°С (EtOH). IR spectrum, ν, cm–1: 1620 (С=О), 2222 (C≡N). 1H NMR spectrum, δ, ppm (J, Hz): 3.89 (3Н, s, OCH3); 7.04 (2Н, d, J = 8.6, H Ar); 7.27 (1Н, t, J = 7.0, H-6); 7.60 (1Н, t, J = 7.8, H-7); 7.75 (1Н, s, H-2); 7.80 (2Н, d, J = 8.6, H Ar); 7.86 (1H, d, J = 8.9, H-8); 9.81 (1H, d, J = 7.0, H-5). 13C NMR spectrum, δ, ppm: 55.6 (OСН3); 83.4 (С-1); 113.9 (C Ar); 115.4 (CN); 116.2; 117.2; 122.5; 128.4; 128.5; 129.0; 131.0; 131.4 (C Ar); 140.5; 162.6 (C Ar); 183.1 (C=O). Mass spectrum, m/z (I rel,%): 276 [М]+ (90), 135 (100). Found, %: С 73.86; Н 4.33; N 10.11. C17H12N2O2. Calculated, %: С 73.90; Н 4.38; N 10.14.