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Synlett 2009(7): 1126-1130  
DOI: 10.1055/s-0029-1216631
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Facile One-Pot Three-Component Synthesis of Macrocyclic Imidazolidines by [3+2] Cycloaddition Reaction of Azomethine Ylides

Subban Kathiravan, Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
Fax: +91(44)22352494; e-Mail: ragharaghunathan@yahoo.com;
Further Information

Publication History

Received 13 January 2009
Publication Date:
02 April 2009 (online)

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Abstract

One-pot three-component synthesis of novel macrocyclic imidazolidines has been accomplished in good yields via a facile [3+2] cycloaddition reaction of azomethine ylide, derived from paraformaldehyde and sarcosine, with various macrocyclic imines as dipolarophiles. The effect of solvent on the [3+2]-dipolar cycloaddition reaction is also studied.

Key words

macrocycle - bisimidazolidine - cycloaddition - azomethine ylide

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Representative Procedure for Dialdehyde 1: A mixture of freshly distilled salicylaldehyde (2 mmol), dibromoethane (1 mmol), anhyd K2CO3 (2 mmol) and KI (0.1 mmol) in anhyd MeCN (20 mL) was refluxed overnight. After completion of the reaction MeCN was distilled off under vacuum. The reaction mixture was then washed with H2O and extracted with CHCl3. The organic layer was concentrated by distillation under reduced pressure to give the required dialdehyde in an excellent yield (97%).

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Representative Experimental Procedure for the Synthesis of Imine Derivative 2: A mixture of dialdehyde 1 (1 mmol), 1,2 diamino ethane (1 mmol), and EtOH (100 mL) was refluxed for 12 h. After completion of the reaction the solvent was carefully removed under reduced pressure to give the required bisimine 2.

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Representative Procedure for the Synthesis of Bisimidazolidine Derivatives 6, 7, 10, 11: A mixture of sarcosine (4.0 equiv), paraformaldehyde (12 equiv) and the corresponding macrocyclic diimine (1 equiv) was heated under reflux in toluene in a Dean-Stark apparatus (10 mL for 1 mmol of dipolarophile). After completion of the reaction as evidenced by TLC the reaction mixture was filtered through a pad of Celite and the solvent was removed under reduced pressure. The crude product was subjected to column chromatography using petroleum ether-EtOAc (3:2) as eluent to get the pure product.

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Macrocyclic Schiff Base 8b: R f = 0.6 (Hex-EtOAc, 3:1); pale yellow solid; yield: 95%; mp 126-129 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 4.12 (s, 4 H), 5.22 (s, 4 H), 6.78-7.80 (m, 12 H), 8.78 (s, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 60.6, 68.1, 112.1, 120.8, 123.6, 125.2, 125.5, 128.3, 128.6, 131.4, 137.7, 159.3. MS: m/z = 366 [M+]. Anal. Calcd for C24H22N2O2: C, 77.79; H, 5.99; N, 7.56; Found: C, 77.84; H, 6.04; N, 7.48.

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Macrocyclic Imidazolidine 6: Rf = 0.5 (Hex-EtOAc, 3:2); yellow liquid; yield: 68%. ¹H NMR (300 MHz, CDCl3): δ = 2.33 (s, 6 H), 2.56 (dd, J = 7.2, 7.5 Hz, 4 H), 3.24 (d, J = 6.3 Hz, 2 H), 3.32 (d, J = 6.3 Hz, 2 H), 4.17-4.29 (m, 4 H), 4.33 (q, J = 4.8 Hz, 4 H), 5.12-5.18 (m, 2 H), 6.77-7.43 (m, 8 H). ¹³C NMR (75 MHz, CDCl3): δ = 40.71, 60.52, 65.60, 71.30, 87.69, 109.85, 120.13, 124.59, 126.98, 130.23, 154.03. MS: m/z = 422.32 [M+]. Anal. Calcd for C24H32N4O2: C, 70.54; H, 7.89; N, 13.72; Found: C, 70.68; H, 7.98; N, 13.84.

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Macrocyclic Imidazolidine 10a: Rf = 0.5 (Hex-EtOAc, 3:2); yellow liquid; yield: 65%. ¹H NMR (300 MHz, CDCl3): δ = 2.35 (s, 6 H), 2.60 (dd, J = 7.2, 7.5 Hz, 4 H), 2.83 (d, J = 6.9 Hz, 2 H), 3.27 (d, J = 6.9 Hz, 2 H), 4.35-4.39 (q, J = 4.8 Hz, 4 H), 5.09 (s, 4 H), 5.19 (t, 2 H), 6.81-7.46 (m, 12 H). ¹³C NMR (75 MHz, CDCl3):
δ = 40.74, 48.43, 52.40, 67.30, 71.43, 110.31, 120.23, 125.94, 127.27, 127.80, 127.93, 128.29, 142.32, 153.57, 161.53. MS: m/z = 484.30 [M+]. Anal. Calcd for C30H36N4O2: C, 74.33; H, 7.49; N, 11.56. Found: C, 74.48; H, 7.60; N, 11.68.

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Macrocyclic Imidazolidine 11b: yellow liquid; yield: 60%. ¹H NMR (300 MHz, CDCl3): δ = 0.79-0.83 (m, 2 H), 2.23-2.33 (m, 4 H), 2.39 (s, 6 H), 2.63 (dd, J = 7.2, 7.2 Hz, 4 H), 2.81 (d, J = 6.3 Hz, 2 H), 2.88 (d, J = 6.0 Hz, 2 H), 4.41 (q, J = 4.8 Hz, 4 H), 5.23 (t, J = 6.9 Hz, 2 H), 6.81-7.47 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 29.35, 41.85, 49.43, 61.63, 69.83, 72.49, 88.81, 111.36, 121.08, 125.53, 125.87, 126.74, 127.99, 128.99, 130.72, 131.38, 137.53, 155.12. MS: m/z = 497.15 [M+]. Anal. Calcd for C31H38N4O2: C, 74.65; H, 7.68; N, 11.24. Found: C, 74.78; H, 7.54; N, 11.32.