Startseite Synthesis of tricyclic indolizidines from ethyl isocyanoacetate
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Synthesis of tricyclic indolizidines from ethyl isocyanoacetate

  • Massimiliano Lamberto EMAIL logo
Veröffentlicht/Copyright: 26. Mai 2015
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Heterocyclic Communications
Aus der Zeitschrift Heterocyclic Communications Band 21 Heft 3

Abstract

Tricyclic indolizidines were synthesized in good yields from commercially available ethyl isocyanoacetate by a novel sequential alkylation, thiol-mediated radical cyclization, N-alkylation, and microwave-assisted Pauson-Khand reaction.

Keywords: indolizidine; isocyanide; isocyanoacetate; Pauson-Khand reaction; radical cyclization

In this communication, we present a novel strategy for the synthesis of tricyclic indolizidines starting from a simple isocyanoacetate and using a radical cyclization/N-alkylation/Pauson-Khand [1–6] cycloaddition strategy. Recently, the synthesis of functionalized indolizidines via Pauson-Khand reaction using a stoichiometric amount of Co2(CO)8, in the presence of various promoters (CO, DMSO, NMO, and TMANO) has been reported [7–9]. Isocyanoacetates [10] have been widely used in many different areas of chemistry as efficient building blocks in the total synthesis of natural products and biologically active molecules. It was envisaged that ethyl isocyanoacetate could be used as the starting building block to access tricyclic indolizidines, useful substrates for the synthesis of indolizidine alkaloids such as asperparaline, and its derivatives (Figure 1), which exhibit potent paralytic, fungicidal, insecticidal, and antifeedant activity [11–13].

Figure 1 Asperparaline and its derivatives.
Figure 1

Asperparaline and its derivatives.

Ethyl isocyanoacetate was first alkylated with excess allyl bromide to give isocyanide 1 in 83% yield [14]. Subsequent microwave-assisted thiol-mediated radical cyclization using 2-mercaptoethanol [15] gave pyroglutamates 2 and 3 in 88% yield (Scheme 1) as a 1:1 inseparable mixture of cis/trans diastereomers. The diastereomeric ratio was determined by 1H NMR.

Scheme 1 Synthesis of pyroglutamates.Reagents and conditions: (i) allyl bromide (2.5 equiv), K2CO3, TBAB, CH3CN, reflux 20 h; (ii) 2-mercaptoethanol (3.0 equiv), AIBN (0.2 equiv) in toluene, MW 130°C 2×5 min.
Scheme 1

Synthesis of pyroglutamates.

Reagents and conditions: (i) allyl bromide (2.5 equiv), K2CO3, TBAB, CH3CN, reflux 20 h; (ii) 2-mercaptoethanol (3.0 equiv), AIBN (0.2 equiv) in toluene, MW 130°C 2×5 min.

The next step in our strategy was the N-alkylation of these substrates with a variety of propargyl bromides that would give access to substrates that could then be subjected to the Pauson-Khand cyclization reaction. Although NaH and NaOH, under phase transfer conditions, are the bases employed for N-alkylation of either proline or pyroglutamates in the literature [16], better yields were obtained using tert-butylimino-tri(pyrrolidino)phosphorane (BTPP). Alkylation of pyroglutamates 2,3 was then performed using BTPP and three different propargyl bromides (RX) in refluxing acetonitrile (Scheme 2). Compounds 4,5 and 8,9 were obtained as inseparable mixtures of diastereomers in 72% yield (1.4:1 cis/trans ratio by 1H NMR) and 99% yield (1.7:1 cis/trans ratio by 1H NMR), respectively. Pyroglutamates 6 and 7, with a terminal Trimrthylsilyl (TMS) group, were obtained in 30% yield only as an inseparable mixture of diastereomers (1.9:1 cis/trans ratio by 1H NMR), due to loss of the TMS group and consequent formation of 8 and 9 (isolated in 31% yield) as a by-product. With these substrates in hand, it was possible to perform the final step in our synthetic strategy, the Pauson-Khand cycloaddition. Substrates 4–9 were first allowed to react with Co2(CO)8, under standard Pauson-Khand reaction conditions (Table 1). Reaction of substrates 8,9 with an equimolar amount of Co2(CO)8 at room temperature, using NMO as promoter, gave only traces of the tricyclic indolizidines 10 and 11, even after a few days. Use of different promoters and even increasing the reaction temperature did not improve the reaction yield. It was then decided to perform the reaction under microwave irradiation [17]. We were delighted to obtain the desired compounds 10 (42%) and 11 (23%) in an overall yield of 65%, in 10 min only and in the absence of promoters. Microwave irradiation was then used to test other substrates. Compounds 12–15 bearing a functionalized terminal alkyne were cyclized in good to excellent yields under microwave irradiation. These indolizidines 12,13 and 14,15 were obtained as inseparable mixtures of two diastereoisomers, 1.2:1 and 2.1:1 cis/trans ratio by 1H NMR, respectively (Table 1).

Scheme 2 Synthesis of alkylated pyroglutamates 4–9.Reagents and conditions: (i) RX (1.5 eq), BTPP (1.5 eq), 12 h at reflux in CH3CN.
Scheme 2

Synthesis of alkylated pyroglutamates 4–9.

Reagents and conditions: (i) RX (1.5 eq), BTPP (1.5 eq), 12 h at reflux in CH3CN.

Table 1

Synthesis of tricyclic indolizidines.

SubstrateConditionsProductYield
8, 9Co2(CO)8 (1.0 eq), NMO (3.0 eq), 2d rt; Co2(CO)8 (1.0 eq), μω 10 min at 100°C
Trace, 65%
4, 5Co2(CO)8 (1.0 eq), μω 10 min at 100°C
56%
6, 7Co2(CO)8 (1.0 eq), μω 10 min at 100°C
87%

In conclusion, tricyclic indolizidines 10–15 were successfully synthesized from a simple and commercially available isocyanide via sequential alkylation/radical cyclization/N-alkylation/microwave-assisted Pauson-Khand cyclization in good yields. The synthesized substrates could be used to access asperparaline and its derivatives.

Experimental details

Flash column chromatography was performed using Sorbsil C60, 40–60-mesh silica gel. Dichloromethane and toluene were distilled from calcium hydride and diethyl ether from sodium wire. 1H NMR spectra (400 MHz) and 13C NMR spectra (100 MHz) were obtained in CDCl3 on a Brucker AVANCE III spectrometer. IR spectra were recorded on a Nicolet Impact 400 using a neat film on a Bio-Rad Golden Gate ATR FT-IR and a FTIR Perkin-Elmer 2000 spectrometers coupled with an AutoIMAGE FTIR microscope. Mass spectrometry data were obtained on a ThermoQuest TraceMS gas chromatograph-mass spectrometer configured for open access and on an LC-MS. Microwave reactions were performed on a CEM Microwave Synthesizer.

2-Allyl-1-(but-2-yn-1-yl)-cis-4-methyl-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester (4) and 2-allyl-1-(but-2-yn-1-yl)-trans-4-methyl-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester (5)  A homogeneous mixture of pyroglutamates 2,3 (554 mg, 2.63 mmol, 1.0 eq), 1-bromobut-2-yne (348 μL, 3.93 mmol, 1.5 eq), BTPP (1.24 mL, 3.93 mmol, 1.5 eq) in dry acetonitrile (30 mL) was heated under reflux with stirring for 12 h. The mixture was then cooled, and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate, 3:1) gave the title compounds 4 and 5 as a yellowish oil (494 mg, 72% yield); inseparable mixture of diastereoisomers (1.4:1); Rf = 0.43. Compound 4: 1H NMR: δ 1.17 (3H, d, J = 7.5 Hz, CH3CH), 1.25 (3H, t, J = 7.0 Hz, CH3CH2O), 1.64 (1H, dd, J = 13.0, 10.5 Hz, CH3CHCHH), 1.73 (3H, t, J = 2.5 Hz, CH3C≡C), 2.33 (1H, dd, J = 13.5, 9.0 Hz, CH3CHCHH), 2.56–2.69 (1H, m, CH3CHCHH), 2.67–2.83 (1H, m, CH2=CHCH2), 3.96 (1H, d, J = 18.0 Hz, NCHH), 4.09–4.21 (3H, m, CH2O and NCHH), 5.15–5.22 (2H, m, CH2CH=CH2), 5.65–5.79 (1H, m, CH2CH=CH2); 13C NMR (CDCl3): δ 3.8, 14.4, 16.4, 30.8, 35.2, 37.2, 38.9, 61.9, 66.4, 73.8, 79.8, 120.6, 132.1, 173.4, 178.0. Compound 5: 1H NMR: δ 1.18 (3H, d, J = 7.5 Hz, CH3CH), 1.26 (3H, t, J = 7.0 Hz, CH3CH2O), 1.73 (3H, t, J = 2.5 Hz, CH3C,1.4:1, C≡C), 1.84 (1H, dd, J = 13.0, 7.0 Hz, CH3CHCHH), 2.32 (1H, dd, J = 13.5, 10.0 Hz, CH3CHCHH), 2.45–2.54 (1H, m, CH3CHCHH), 2.67–2.83 (1H, m, CH2=CHCH2), 3.95 (1H, d, J = 18.0 Hz, NCHH), 4.09–4.21 (3H, m, CH2O and NCHH), 5.15–5.22 (2H, m, CH2CH=CH2), 5.65–5.79 (1H, m, CH2CH=CH2); 13C NMR: δ 3.8, 14.4, 17.3, 31.3, 35.4, 36.6, 39.6, 62.0, 67.4, 74.1, 80.0, 120.6, 132.2, 173.6, 177.9; IR: νmax 1736, 1711, 1368, 1305, 1251, 1204, 1140 cm-1: GC/CI-MS: m/z 322 (92%), [M+H]+; retention time 13.87 min. HRMS (ESI+). Calcd for C15H21NO3Na [M+Na]+: m/z 344.1652. Found: m/z 344.1654.

2-Allyl-cis-4-methyl-5-oxo-1-(3-trimethylsilanyl-prop-2-yn-1-yl)-pyrrolidine-2-carboxylic acid ethyl ester (6) and 2-allyl-trans-4-methyl-5-oxo-1-(3-trimethylsilanyl-prop-2-yn-1-yl)-pyrrolidine-2-carboxylic acid ethyl ester (7)  A homogeneous mixture of pyroglutamates 2, 3 (560 mg, 2.65 mmol, 1.0 eq), (3-bromoprop-1-ynyl)trimethylsilane (636 μL, 3.98 mmol, 1.5 eq), BTPP (1.25 mL, 3.98 mmol, 1.5 eq) in dry acetonitrile (30 mL) was heated under reflux with stirring for 12 h. The mixture was then cooled, and the solvent removed in vacuo. Purification by flash chromatography (hexane/ethyl acetate, 3:1) gave the title compounds 6 and 7 as a yellowish oil (249 mg, 30% yield); inseparable mixture of diastereoisomers (1.9:1); Rf = 0.5. Compound 6: 1H NMR: δ 0.09 (9H, s, (CH3)3Si), 1.16 (3H, d, J = 7.0 Hz, CH3CH), 1.23 (3H, t, J = 7.0 Hz, CH3CH2O), 1.64 (1H, dd, J = 13.0, 10.5 Hz, CH3CHCHH), 2.33 (1H, dd, J = 13.0, 8.5 Hz, CH3CHCHH), 2.46–2.57 (1H, m, CH3CHCHH), 2.61–2.90 (1H, m, CH2=CHCH2), 3.93 (1H, d, J = 18.0 Hz, NCHH), 4.12 (2H, q, J = 7.0 Hz, CH2O), 4.36 (1H, d, J = 18.0 Hz, NCHH), 5.12–5.22 (2H, m, CH2CH=CH2), 5.67–5.82 (1H, m, CH2CH=CH2); 13C NMR: δ 0.0, 14.3, 16.3, 31.4, 35.1, 37.1, 38.8, 61.7, 66.6, 88.7, 100.4, 120.4, 132.2, 173.1, 177.8; GC/CI-MS: m/z 264 (30%), [M+H]+, 190 (100%), [M-TMS]+; retention time 13.49 min. Compound 7: 1H NMR: δ 0.08 (9H, s, (CH3)3Si), 1.15 (3H, d, J = 7.0 Hz, CH3CH), 1.25 (3H, t, J = 7.0 Hz, CH3CH2O), 1.79 (1H, dd, J = 13.5, 7.5 Hz, CH3CHCHH), 2.33 (1H, dd, J = 13.0, 8.5 Hz, CH3CHCHH), 2.46–2.57 (1H, m, CH3CHCHH), 2.61–2.90 (1H, m, CH2=CHCH2), 3.92 (1H, d, J = 18.0 Hz, NCHH), 4.16 (2H, q, J = 7.0 Hz, CH2O), 4.35 (1H, d, J = 18.0 Hz, NCHH), 5.12–5.22 (2H, m, CH2CH=CH2), 5.67–5.82 (1H, m, CH2CH=CH2); 13C NMR: δ 0.0, 14.4, 17.2, 31.7, 35.0, 36.8, 39.6, 61.9, 67.4, 88.9, 100.7, 120.4, 132.3, 173.4, 177.6; IR: νmax 1733, 1697, 1456, 1394, 1304, 1256, 1199 cm-1; GC/MS: m/z 264 (30%), [M+H]+, 190 (100%), [M-TMS]+; retention time 13.53 min. HRMS (ES+). Calcd for C17H28NO3Si, [M+H]+: m/z 264.1594. Found: m/z 264.1597.

2-Allyl-cis-4-methyl-5-oxo-1-prop-2-yn-1-yl-pyrrolidine- 2-carboxylic acid ethyl ester (8) and 2-allyl-trans-4-methyl-5-oxo-1-prop-2-yn-1-yl-pyrrolidine-2-carboxylic acid ethyl ester (9)  A homogeneous mixture of pyroglutamates 2/3 (208 mg, 0.99 mmol, 1.0 eq), 3-Bromopropyne (165 μL, 1.48 mmol, 1.5 eq), BEMP (436 μL, 1.48 mmol, 1.5 eq) in dry acetonitrile (10 mL) was heated under reflux with stirring for 12 h. The reaction mixture was then cooled, and the solvent removed in vacuo. Purification by flash chromatography eluting with hexane/ethyl acetate (4:1) gave the title compounds 8 and 9 as a yellowish oil (200 mg, 82% yield); 1.7:1 inseparable mixture of diastereoisomes (1.7:1); Rf = 0.35. Compound 8: 1H NMR: δ 1.19 (3H, d, J = 7.0 Hz, CH3CH), 1.26 (3H, t, J = 7.0 Hz, CH3CH2O), 1.66 (1H, dd, J = 13.0, 10.5 Hz, CH3CHCHH), 2.15 (1H, t, J = 2.5 Hz, CH≡CCH2N), 2.41 (1H, dd, J = 12.5, 8.5 Hz, CH3CHCHH), 2.48–2.62 (1H, m, CH3CHCHH), 2.65–2.82 (1H, m, CH2=CHCH2), 3.99–4.28 (2H, m, NCH2), 4.10–4.16 (2H, m, CH2O), 5.21 (2H, m, CH2CH=CH2), 5.74 (1H, m, CH2CH=CH2); 13C NMR: δ 14.4, 16.3, 30.5, 35.2, 37.4, 39.3, 62.0, 66.6, 72.0, 78.8, 120.8, 131.8, 173.1, 178.0; GC/CI-MS: m/z 250 (100%), [M+H]+; retention time 11.79 min. Compound 9: 1H NMR: δ 1.25 (3H, d, J = 7.0 Hz, CH3CH), 1.29 (3H, t, J = 7.0 Hz, CH3CH2O), 1.89 (1H, dd, J = 13.0, 7.0 Hz, CH3CHCHH), 2.16 (1H, t, J = 2.5 Hz, CH≡CCH2N), 2.34 (1H, dd, J = 13.5, 10.0 Hz, CH3CHCHH), 2.48–2.62 (1H, m, CH3CHCHH), 2.65–2.82 (1H, m, CH2=CHCH2), 3.99–4.28 (2H, m, NCH2), 4.10–4.16 (2H, m, CH2O), 5.21 (2H, m, CH2CH=CH2), 5.74 (1H, m, CH2CH=CH2); 13C NMR: δ 14.4, 17.2, 30.9, 35.1, 36.7, 39.7, 62.1, 67.4, 71.8, 79.1, 120.8, 132.0, 173.4, 177.8; IR: νmax 1728, 1693, 1455, 1390, 1302, 1212, 1154 cm-1; GC/CI-MS: m/z 250 (1000%), [M+H]+; retention time 11.94 min. HRMS (ESI+). Calcd for C14H19NO3Na [M+Na]+: m/z 272.1257. Found: m/z 272.1258.

cis-2-Methyl-3,6-dioxo-2,3,6,7,7a,8-hexahydro-1H, 4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (10) andtrans-2-methyl-3,6-dioxo-2,3,6,7,7a,8-hexahydro-1H,4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (11)  To a heavy-walled Pyrex tube were added pyroglutamates 8, 9 (113 mg, 0.45 mmol, 1.0 eq) and dicobaltoctacarbonyl (155 mg, 0.45 mmol, 1.0 eq) in 3 mL of dry toluene. The Pyrex tube was then capped, and the reaction mixture was flushed with nitrogen. Heating was then applied by means of microwave irradiation (100°C) for 10 min. The tube was then allowed to cool for a couple of minutes, and mixture was then filtered on celite, and the solvent removed under reduced pressure. Purification by flash chromatography eluting with ethyl acetate afforded the title compounds 10 (52 mg, 42%, Rf = 0.64) and 11 (29 mg, 23%, Rf = 0.58) as colorless liquids. Compound 10: 1H NMR: δ 1.17 (3H, d, J = 7.0 Hz, CH3CH), 1.23–1.30 (1H, m, CHHCO), 1.28 (3H, t, J = 7.0 Hz, CH3CH2O), 1.56 (1H, dd, J = 12.5, 10.0 Hz, CH3CHCHH), 2.00 (1H, dd, J = 18.5, 2.5 Hz, CHHCHCH2), 2.50–2.56 (1H, m, CH3CH), 2.61 (1H, dd, J = 12.5, 8.5 Hz, CH3CHCHH), 2.62 (1H, dd, J = 18.5, 6.5 Hz, CHHCHCH2), 2.78–2.84 (1H, m, CH2CHCH2), 2.86 (1H, dd, J = 12.5, 5.0 Hz, CHHCO), 3.80 (1H, d, J = 16 Hz, NCHH), 4.24 (2H, q, J = 7.0 Hz, CH2O), 4.97 (1H, d, J = 16 Hz, NCHH), 6.01 (1H, s, C=CH); 13C NMR: δ 14.6, 16.1, 35.8, 37.7, 40.9, 41.4, 41.5, 42.0, 62.6, 64.9, 129.3, 172.3, 172.9, 176.5, 207.1; IR: νmax 1707, 1455, 1384, 1302, 1274, 1195, 1021 cm-1; GC/CI-MS: m/z 278 (60%), [M+H]+. HRMS (EI). Calcd for C15H19NO4 (M)+: m/z 277.13141. Found: m/z 277.13061. Compound 11: 1H NMR: δ 1.21 (3H, d, J = 7.0 Hz, CH3CH), 1.31–1.37 (1H, m, CHHCO), 1.32 (3H, t, J = 7.0 Hz, CH3CH2O), 1.97–2.02 (2H, m, CH3CHCHH and CHHCHCH2), 2.26 (1H, dd, J = 13.5, 9.5 Hz, CH3CHCHH), 2.52–2.58 (1H, m, CH3CH), 2.63 (1H, dd, J = 18.5, 6.5 Hz, CHHCHCH2), 2.78 (1H, dd, J = 12.5, 5.0 Hz, CHHCO), 2.79–2.87 (1H, m, CH2CHCH2), 3.92 (1H, d, J = 16.0 Hz, NCHH), 4.28 (2H, q, J = 7.0 Hz, CH2O), 5.05 (1H, d, J = 16.0 Hz, NCHH), 6.01 (1H, s, C=CH); 13C NMR: δ 14.6, 17.5, 35.9, 37.8, 38.7, 41.4, 41.6, 41.9, 62.5, 65.3, 129.2, 172.3, 173.5, 176.7, 206.9; IR: νmax 1705, 1455, 1388, 1278, 1195, 1022 cm-1; GC/CI-MS: m/z 278 (45%), [M+H]+.

cis-2,5-Dimethyl-3,6-dioxo-2,3,6,7,7a,8-hexahydro-1H, 4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (12) andtrans-2, 5-dimethyl-3,6-dioxo-2,3,6,7,7a,8-hexahydro-1H, 4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (13)  To a heavy-walled Pyrex tube were added pyroglutamates 4, 5 (98 mg, 0.37 mmol, 1.0 eq) and dicobaltoctacarbonyl (127 mg, 0.37 mmol, 1.0 eq) in 2.5 mL of dry toluene. The tube was then capped, and the mixture was flushed with nitrogen. Heating was then applied by means of microwave irradiation (100°C) for 10 min. The tube was then allowed to cool for a couple of minutes; the mixture was then filtered on celite, and the solvent removed under reduced pressure. Purification by flash chromatography eluting with ethyl acetate afforded the title compounds 12 and 13 (61 mg, 56%, Rf = 0.67) as colorless liquid (1.2:1 diastereomeric ratio by NMR). Compound 12: 1H NMR: δ 1.19 (3H, d, J = 7.0 Hz, CH3CH), 1.24–1.27 (1H, m, CHHCO), 1.32 (3H, t, J = 7.0 Hz, CH3CH2O), 1.56 (1H, dd, J = 12.0, 10.5 Hz, CH3CHCHH), 1.74 (3H,s, C=CCH3), 1.93–2.03 (1H, m, CHHCHCH2), 2.51–2.57 (1H, m, CH3CH), 2.61 (1H, dd, J = 12.5, 8.5 Hz, CH3CHCHH), 2.61–2.67 (1H, m, CHHCHCH2), 2.66–2.73 (1H, m, CH2CHCH2), 2.85 (1H, dd, J = 12.5, 4.5 Hz, CHHCO), 3.74 (1H, d, J = 16.0 Hz, NCHH), 4.27 (2H, q, J = 7.0 Hz, CH2O), 5.00 (1H, d, J = 16.0 Hz, NCHH); 13C NMR: δ 8.3, 14.7, 16.1, 35.8, 36.1, 38.9, 39.9, 40.7, 42.0, 62.5, 65.2, 136.1, 163.7, 173.1, 176.6, 207.5; GC/CI-MS: m/z 292 (100%), [M+H]+. Compound 13: 1H NMR: δ 1.21 (3H, d, J = 7.0 Hz, CH3CH), 1.24–1.27 (1H, m, CHHCO), 1.31 (3H, t, J = 7.0 Hz, CH3CH2O), 1.73 (3H,s, C=CCH3), 1.93–2.03 (2H, m, CH3CHCHH and CHHCHCH2), 2.24 (1H, dd, J = 13.5, 9.5 Hz, CH3CHCHH), 2.51–2.57 (1H, m, CH3CH), 2.61–2.73 (2H, m, CHHCHCH2 and CH2CHCH2), 2.75 (1H, dd, J = 12.5, 5.0 Hz, CHHCO), 3.84 (1H, d, J = 16.0 Hz, NCHH), 4.26 (2H, q, J = 7.0 Hz, CH2O), 5.06 (1H, d, J = 16.0 Hz, NCHH); 13C NMR: δ 8.3, 14.6, 17.5, 35.9, 36.0, 38.9, 39.8, 41.0, 41.9, 62.5, 65.6, 136.1, 163.8, 173.7, 176.8, 207.3; IR: νmax 1705, 1456, 1395, 1301, 1199, 1022 cm-1; GC/CI-MS: m/z 292 (100%), [M+H]+. HRMS (EI). Calcd for C16H20NO4 (M-H)-: m/z 290.13923. Found: m/z 290.13892; IR.

cis-2-Methyl-3,6-dioxo-5-trimethylsilanyl-2,3,6,7,7a,8-hexahydro-1H,4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (14) andtrans-2-methyl-3,6-dioxo-5-trimethylsilanyl-2,3,6,7,7a,8-hexahydro-1H,4H-3a-aza-s-indacene-8a-carboxylic acid ethyl ester (15)  To a heavy-walled Pyrex tube were added pyroglutamates 6, 7 (68 mg, 0.211 mmol, 1.0 eq) and dicobaltoctacarbonyl (72.5 mg, 0.21 mmol, 1.0 eq) in 2.5 mL of dry toluene. The tube was then capped, and the reaction mixture was flushed with nitrogen. Heating was then applied by means of microwave irradiation (100°C) for 10 min. The tube was then allowed to cool for a couple of minutes; the mixture was then filtered on celite, and the solvent removed under reduced pressure. Purification by flash chromatography eluting with ethyl acetate afforded the title compounds 14 and 15 (62 mg, 87%, Rf = 0.73) as colorless liquid (2.1:1 diastereomeric ratio by NMR). Compound 14: 1H NMR: δ 0.23 (9H, s, (CH3)3Si), 1.19 (3H, d, J = 7.0 Hz, CH3CH), 1.21–1.27 (1H, m, CHHCO), 1.29 (3H, t, J = 7.0 Hz), 1.56 (1H, t, J = 10.0 Hz, CH3CHCHH), 1.89–2.01 (1H, m, CHHCHCH2), 2.50–2.62 (3H, m, CH3CHCHH and CHHCHCH2), 2.72–2.77 (1H, m, CH2CHCH2), 2.85 (1H, dd, J = 12.5, 4.5 Hz, CHHCO), 3.75 (1H, d, J = 16.0 Hz, NCHH), 4.25 (2H, q, J = 7.0 Hz, CH2O), 5.17 (1H, d, J = 16.0 Hz, NCHH); 13C NMR: δ 0.3, 14.4, 16.0, 31.9, 35.8, 38.6, 39.3, 40.8, 41.7, 41.9, 62.4, 64.7, 140.4, 173.0, 178.3, 211.2; GC/CI-MS: m/z 350 (66%), [M+H]+. Compound 15: 1H NMR: δ 0.23 (9H, s, (CH3)3Si), 1.20 (3H, d, J = 7.0 Hz, CH3CH), 1.21–1.27 (1H, m, CHHCO), 1.30 (3H, t, J = 7.0 Hz), 1.89–2.01 (2H, m, CH3CHCHH and CHHCHCH2), 2.25 (1H, dd, J = 13.5, 10.0 Hz, CH3CHCHH), 2.50–2.62 (2H, m, CH3CHCH2 and CHHCHCH2), 2.72–2.77 (1H, m, CH2CHCH2), 2.85 (1H, dd, J = 12.5, 4.5 Hz, CHHCO), 3.84 (1H, d, J = 16.0 Hz, NCHH), 4.25 (2H, q, J = 7.0 Hz, CH2O), 5.24 (1H, d, J = 16.0 Hz, NCHH); 13C NMR: δ 0.3, 14.6, 17.4, 31.2, 35.8, 38.6, 39.4, 40.8, 41.8, 42.0, 62.4, 65.0, 140.3, 173.5, 178.4, 211.1; IR: νmax 1731, 1690, 1603, 1454, 1402, 1247, 1193, 1023 cm-1; GC/CI-MS: m/z 350 (50%), [M+H]+. HRMS (ES+). Calcd for C18H27NO4SiNa (M+Na)+: m/z 372.1601. Found: m/z 372.1607.

Corresponding author: Massimiliano Lamberto, Department of Chemistry and Physics, Monmouth University, West Long Branch, NJ 07764, USA, e-mail:

Acknowledgments

The author would like to thank Professor Jeremy D. Kilburn for providing useful insights and comments that greatly assisted the research and Monmouth University for funding.

References

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Received: 2015-3-24
Accepted: 2015-4-5
Published Online: 2015-5-26
Published in Print: 2015-6-1

©2015 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Synthesis of quinazolines and quinazolinones via palladium-mediated approach
  4. Media with photoinduced irreversible fluorescence
  5. Synthesis of quinolines and acridines by the reaction of 2-(perfluoroalkyl)anilines with lithium and Grignard reagents
  6. Preliminary Communications
  7. Synthesis of tricyclic indolizidines from ethyl isocyanoacetate
  8. Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones
  9. Research Articles
  10. Preparation of optically active 4-substituted γ-lactones by lipase-catalyzed optical resolution
  11. One-pot synthesis of 4-alkyl-2-amino-4H-chromene derivatives
  12. Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones
https://doi.org/10.1515/hc-2015-0047
Schlagwörter für diesen Artikel
indolizidine; isocyanide; isocyanoacetate; Pauson-Khand reaction; radical cyclization
Creative Commons
BY-NC-ND 3.0

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Synthesis of quinazolines and quinazolinones via palladium-mediated approach
  4. Media with photoinduced irreversible fluorescence
  5. Synthesis of quinolines and acridines by the reaction of 2-(perfluoroalkyl)anilines with lithium and Grignard reagents
  6. Preliminary Communications
  7. Synthesis of tricyclic indolizidines from ethyl isocyanoacetate
  8. Ligand- and catalyst-free intramolecular C-S bond formation: direct access to indalothiochromen- 4-ones
  9. Research Articles
  10. Preparation of optically active 4-substituted γ-lactones by lipase-catalyzed optical resolution
  11. One-pot synthesis of 4-alkyl-2-amino-4H-chromene derivatives
  12. Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones
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