Multicomponent Synthesis of Pentyl-Sulfonyl Amidines via Diazoalkane

Alessandro Contini; Emanuela Erba; Sara Pellegrino

doi:10.1055/s-0031-1290667

Synlett, Inhaltsverzeichnis

Synlett 2012; 23(10): 1523-1525
DOI: 10.1055/s-0031-1290667

letter

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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Abstract

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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

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Referenzen

References and Notes

1a Clerici F, Gelmi ML, Rossi LM. Synthesis 1987; 1025
1b Battistini M, Erba E, Pocar D. Synthesis 1992; 1206
1c Pocar D, Roversi E, Trimarco P, Valgattarri G. Liebigs Ann. 1995; 487
1d Erba E, Pocar D, Trimarco P. J. Chem. Soc., Perkin Trans. 1 1998; 3535
1e Beccalli EM, Contini A, Trimarco P. Eur. J. Org. Chem. 2003; 3976

2 Greenhill JV, Lue P. Prog. Med. Chem. 1993; 30: 203

3a Body GV In The Chemistry of Amidine and Imidates . Vol. 2, Chap. 8. Patai S, Rappoport Z. Wiley; New York: 1991
3b Barker J, Kilner M. Coord. Chem. Rev. 1994; 133: 219

4 Lee MY, Kim MH, Kim J, Kim SH, Kim BT, Jeong IH, Chang S, Chang SY. Bioorg. Med. Chem. Lett. 2010; 20: 541

5a Cassani F, Celentano G, Erba E, Pocar D. Synthesis 2004; 1041
5b Fusco R, Bianchetti G, Pocar D, Ugo R. Chem. Ber. 1963; 802

6 Contini A, Erba E, Trimarco P. ARKIVOC 2008; (xii): 136
7 Bae I, Han H, Chang S. J. Am. Chem. Soc. 2005; 2038
8 Liu MT. H. Chem. Soc. Rev. 1982; 127
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
10 Pilari T, Tron GC, Masson G, Zhu J. Org. Lett. 2007; 5275