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Synlett 2012; 23(10): 1523-1525
DOI: 10.1055/s-0031-1290667
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© Georg Thieme Verlag Stuttgart · New York

Multicomponent Synthesis of Pentyl-Sulfonyl Amidines via Diazoalkane

Alessandro Contini
DISMAB-Sez. di Chimica Organica ‘Alessandro Marchesini’, Via G. Venezian, 21, 20133 Milano, Italy, Fax: +39(02)50314476   Email: emanuela.erba@unimi.it
,
Emanuela Erba*
DISMAB-Sez. di Chimica Organica ‘Alessandro Marchesini’, Via G. Venezian, 21, 20133 Milano, Italy, Fax: +39(02)50314476   Email: emanuela.erba@unimi.it
,
Sara Pellegrino
DISMAB-Sez. di Chimica Organica ‘Alessandro Marchesini’, Via G. Venezian, 21, 20133 Milano, Italy, Fax: +39(02)50314476   Email: emanuela.erba@unimi.it
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Further Information

Publication History

Received: 28 February 2012

Accepted after revision: 28 March 2012

Publication Date:
25 May 2012 (online)

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Abstract

A series of pentyl-sulfonyl amidines was obtained using a multicomponent synthesis process. The rearrangement of unstable tosylazide–cyclopentanonenamine cycloadducts yielded a diazoalkane intermediate. This primary, unstable reaction product showed good reactivity with certain acid compounds in order to form the corresponding derivatives.

Key words

sulfonyl amidines - multicomponent reaction - diazo­alkane - amino acids - antiresorptive agent
 

  • References and Notes


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  • 9 General Procedure for the Preparation of Amidine 2a–e The proline methyl ester hydrochloride (1 g, 0.006 mol) was suspended in toluene (20 mL), and an equivalent amount of NaOMe (6 mL of 1 M solution) was added. After 30 min the solvent was concentrated to 10 mL under vacuum, and 5 g of molecular sieves were added. To the stirred mixture were added at first cyclopentanone (0.5 g, 0.006 mol) and after 15 min tosylazide (0.92 g, 0.006 mol). The reaction was monitored with TLC (EtOAc–hexane = 1:1), and after 15 min the tosylazide was completely disappeared. The suitable reactant was added (0.012 mol), and the stirring was continued for 1 h. Then the mixture was filtered, and toluene was removed under vacuum. The crude was dissolved in CH2Cl2, washed with H2O (10 mL), dried with Na2SO4, filtered, and the filtrate concentrated in vacuo. The crude was purified by silica gel chromatography (EtOAc–hexane = 1:1) affording the pure amidines 1a,b and 2a–e Methyl 1-[5-Chloro-1(tosylimino)pentyl]pyrrolidine-2-carboxylate (1) Colorless oil (1.68 g, 70%); [α]D –79.8 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.92–2.08 (m, 6 H, 3 CH2), 2.09–2.19 and 2.20–2.28 (2 m, 2 H, CH2), 2.40 (s, 3 H, CH3Ph), 2.85–2.92 and 2.99–3.08 (2 m, 2 H, CH2), 3.49 (s, 3 H, OCH3), 3.58–3.64 (m, 2 H, CH2Cl), 3.61–3.68 and 3.73–3.80 (2 m, 2 H, CH2N), 4.49–4.54 (m, 1 H, CH), 7.25(d, J = 8.20 Hz, 2 H, ArH), 7.77 (d, J = 8.20 Hz, 2 H, ArH). 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 23.6 (CH2), 24.8 (CH2), 29.3 (CH2), 31.6 (CH2), 32.3 (CH2), 44.5 (CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 126.3 (CH), 129.3 (CH), 141.3 (C), 142.1 (C), 166.6 (C), 172.0 (C). ESI-HRMS: m/z calcd for C18H25ClN2O4S: 400.1223; found: 400.1220. Methyl 1-[5-(Benzoyloxy)-1-(tosylimino)pentyl]-pyrrolidine-2-carboxylate (2a) Colorless oil (1.8g, 65%); [α]D –67.8 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.82–2.25 (m, 6 H, 3 CH2), 2.37 (s, 3 H, CH3Ph), 2.87–3.13 (m, 2 H, CH2), 3.45 (s, 3 H, OCH3), 3.50–3.75 (m, 3 H, CH2), 4.34–4.401 (m, 2 H, OCH2), 4.42–4.51 (m, 1 H, CH), 7.20 (d, J = 8.20 Hz, 2 H, ArH), 7.30–7.60 (m, 3 H, ArH), 7.73–7.85 (m, 2 H, ArH), 8.00 (d, J =8.20 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 23.2 (CH2), 24.8 (CH2), 28.9 (CH2), 29.3 (CH2), 32.1 (CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 64.4 (CH2), 126.4 (CH), 128.6 (CH), 129.1 (CH), 129.8 (CH), 130.5 (C), 133.1 (CH), 141.4 (C), 142.0 (C), 166.7 (C), 172.0 (C). ESI-HRMS: m/z calcd for C25H30N2O6S: 486.1824; found: 486.1822. 1-[5-Acetyloxy-1-(tosylimino)pentyl]pyrrolidine-2-carboxylate (2b) Colorless oil (1.8g, 72%); [α]D –80.9 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.78–2.24 (m, 8 H, 4 CH2), 2.05 (s, 3 H, CH3CO), 2.38 (s, 3 H, CH3), 2.89–3.18 (m, 2 H, CH2), 3.46 (s, 3 H, CH3O), 3.53–3.76 (m, 2 H, CH2), 4.07–5.18 (m, 2 H, CH3O), 4.46–4.52 (m, 1 H, CH), 7.22 (d, J =8.20 Hz, 2 H, ArH), 7.74 (d, J = 8.20 Hz, 2 H, ArH). 13C NMR (50MHz, CDCl3): δ = 21.2 (CH3), 21.6 (CH3), 23.2 (CH2), 24.8 (CH2), 28.8 (CH2), 29.3 (CH2), 32.1 (CH2), 48.1 (CH2), 52.3 (CH3), 61.1 (CH), 63.9 (CH2), 126.4 (CH), 129.1 (CH), 141.3 (C), 142.1 (C), 166.7 (C), 172.0 (C). ESI-HRMS: m/z calcd for C20H28N2O6S: 424.1668; found: 424.1666. Methyl 1-[1-(Tosylimino)-5-(tosyloxy)pentyl]-pyrrolidine-2-carboxylate (2c) This reaction was performed in cyclohexane. Colorless oil (1.9 g, 62%); [α] –78.2 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.70–2.26 (m, 8 H, 4 CH2), 2.37 and 2.44 (2 s, 6 H, 2 CH3Ph), 2.91–2.99 (m, 2 H, CH2), 3.45 (s, 3 H, CH3O), 3.46–3.74 (m, 2 H, CH2), 4.02–4.08 (m, 2 H, CH2O), 4.43–4.49 (m, 1 H, CH), 7.21 (d, J = 8.16 Hz, 2 H, ArH), 7.35 (d, J = 8.10 Hz, 2 H, ArH), 7.71 (d, J = 8.16 Hz, 2 H, ArH), 7.78 (d, J = 8.10 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 21.8 (CH3), 22.5 (CH2), 24.8 (CH2), 28.9 (CH2), 29.3 (CH2), 31.7 (CH2), 48.2 (CH2), 52.2 (CH3), 61.1 (CH), 70.0 (CH2), 126.3 (CH), 128.1 (CH), 129.3 (CH), 130.2 (CH), 133.1 (C), 141.3 (C), 142.1 (C), 145.1 (C), 166.4 (C), 171.9 (C). ESI-HRMS: m/z calcd for C25H37N2O7S2: 536.1650; found: 536.1651. Methyl 1-{5-[(2-{[(tert-Butoxy)carbonyl]amino}-propanoyl)oxy]-1-(tosylimino)pentyl}pyrrolidine-2-carboxylate (2d) Colorless oil (2.1, 65%); [α]D –2.29 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.39–144 (m, 12 H, 4 CH3), 1.85–2.29 (m, 8 H, 4 CH2), 2.37 (s, 3 H, CH3Ph), 2.82–3.21 (m, 2 H, CH2), 3.45 (s, 3 H, CH3O), 3.46–3.75 (m, 2 H, CH2), 4.05–4.25 (m, 3 H, CH and CH2), 4.43–4.49 (m, 1 H, CH), 5.08–5.15 (m, 1 H, NH), 7.22 (d, J = 8.18 Hz, 2 H, ArH), 8.73 (d, J = 8.18 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ = 18.8 (CH3), 21.6 (CH3), 23.0 (CH2), 24.8 (CH2), 28.5 (CH3), 29.3 (CH2), 32.0 (CH2), 48.1 (CH2), 49.5 (CH3), 52.2 (CH3), 61.1 (CH), 64.6 (CH2), 79.9 (C), 126.4 (CH), 129.1 (CH), 141.3 (C), 142.1 (C), 155.4 (C), 166.6 (C), 172.0 (C), 173.6 (C). ESI-HRMS: m/z calcd for C26H39N3O8S: 553.2457; found: 553.2458. Methyl 1-[5(4-Nitrophenyloxy)-1-(tosylimino)pentyl]-pyrrolidine-2-carboxylate (2e) Colorless oil (1.0g, 35%); [α]D –99.5 (c 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.82–2.23 (m, 8 H, 4 CH2), 2.37 (s, 3 H, CH3Ph), 2.87–3.12 (m, 2 H, CH2), 3.45 (s, 3 H, CH3), 3.54–3.73 (m, 2 H, CH2), 4.05–4.21 (m, 2 H, CH2), 4.45–4.51 (m, 1 H, CH), 6.94 (d, J = 8.16 Hz, 2 H, ArH), 7.20 (d, J = 8.06 Hz, 2 H, ArH), 7.73 (d, J = 8.06 Hz, 2 H, ArH), 8.19 (d, J = 8.16 Hz, 2 H, ArH). 13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 23.2 (CH2), 24.8 (CH2), 29.0 (CH2), 29.3 (CH2), 32.1 (CH2), 48.1 (CH2), 52.2 (CH3), 61.1 (CH), 68.3 (CH2), 114.7 (CH2), 126.1 (CH), 126.35 (CH), 129.2 (CH), 129.3 (CH), 141.3 (C), 141.7 (C), 142.1 (C), 164.2 (C), 166.5 (C), 172.0 (C). ESI-HRMS: m/z calcd for C24H29N3O7S: 503.1726; found: 503.1724. 5-Morpholino-5-(tosylimino)pentyl Benzoate (2f) Morpholine (0.2 g, 0.0023 mol) and cyclopentanone (0.19 g, 0.0023 mol) were dissolved in CH2Cl2 (10 mL), and 2 g of molecular sieves were added. The mixture was stirred for 30 min, and tosylazide (0.35 g, 0.0023 mol) was added. After 15 min benzoic acid (0.56 g, 0.0046 mol) was added, and the stirring was continued for 1 h. Then the mixture was filtered, washed with H2O (10 mL), dried with Na2SO4, filtered, and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography (EtOAc–hexane = 1:1) affording the pure 2f. Colorless oil (0.68g, 68%). 1H NMR (200 MHz, CDCl3): δ = 1.64–2.01 (4 H, m, 2 CH2), 2.38 (3 H, s, CH3Ph), 2.97–3.10 (2 H, m, CH2), 3.42–3.78 (8 H, m, 4 CH2-morpholine), 4.25–4.39 (2 H, m, CH2O), 7.23 (2 H, d, J = 8.20 Hz, ArH), 7.42–7.61 (3 H, m, ArH), 7.90 (2 H, d, J = 8.15 Hz, ArH), 8.02 (2 H, d, J = 8.20 Hz, ArH). 13C NMR (50 MHz, CDCl3): δ = 21.6 (CH3), 23.8 (CH2), 28.9 (CH2), 30.3 (CH2), 45.0 (CH2), 46.8 (CH2), 64.1 (CH2), 66.5 (CH2), 66.7 (CH2), 126.4 (CH), 128.7 (CH), 129.4 (CH), 129.7 (CH), 130.4 (C), 133.3 (CH), 141.4 (C), 142.3 (C), 166.7 (C), 167.4 (C). ESI-HRMS: m/z calcd for C23H28N2O5S: 444.1718; found: 444.1719
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