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

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

References and Notes

• 1a Von Nussbaum F. Brands M. Hinzen B. Weigand S. Häbich D. Angew. Chem. Int. Ed.  2006,  45:  5072 
• 1b Gibson SE. Lecci C. Angew. Chem. Int. Ed.  2006,  45:  1364 
• 1c Kahne D. Leimkuhler C. Lu W. Walsh C. Chem. Rev.  2005,  105:  425 
• 1d Hruby VJ. Al-Obeidi F. Kazmierski W. Biochem. J.  1990,  268:  249 
• 1e Kessler H. Angew. Chem., Int. Ed. Engl.  1982,  21:  512 
• 2a Chang-Fong J. Benamour K. Szymonski B. Thomasson F. Morand JM. Cussac M. Chem. Pharm. Bull.  2000,  48:  729 
• 2b Sage CR. Michelistich MD. Stout J. Biermann D. Nissen R. Finer-Moore N. Stroud RM. Biochemistry  1998,  37:  13893 
• 3a Sharma V. Crankshaw CL. Piwnica-Worms D.
  J. Med. Chem.  1996,  39:  3483 
• 3b Sage CR. Michelitsch MD. Stout TJ. Blermann D. Nissen R. Finer-Moore J. Stroud RM. Biochemistry  1998,  37:  13893 
• 3c Olmos G. Rinera J. Varcia-Sevilla HA. Eur. J. Pharm.  1996,  310:  273 
• 3d Chang-Fong J. Benamour K. Szymonski B. Thomasson F. Morangd JM. Cussac M. Chem. Pharm. Bull.  2000,  48:  729 
• 3e Sakuta H. Okamotto K. Eur. J. Pharm.  1994,  259:  223 
• 4a Sharma V. Khan MSY. Eur. J. Med. Chem.  2001,  36:  651 
• 4b Kalyaham N. Sparthasarathy PC. Ananthan L. Manjunatha SG. Likhate MA. Indian J. Chem. Sect. B: Org. Chem. Incl. Med. Chem.  1992,  31:  243 
• 5a Van Hook JO, and Craig WE. inventors; U.S. Patent,  2675387.  ; Chem. Abstr. 1955, 49, 4729
• 5b Craig WE, and Van Hook JO. inventors; U.S. Patent,  2675381.  ; Chem. Abstr. 1956, 50, 411
• 6a Li X. Bera M. Musie GT. Powell DR. Inorg. Chim. Acta  2007, 
• 6b Li J. Wang S. Hu J. Chein H. Tetrahedron Lett.  1999,  40:  1961 
• 7 Erkizia E. Aldaba E. Vara Y. Arrieta A. Gornitzka H. Cossio FP. ARKIVOC  2005,  (ix):  189 
• 8 Saegusa T. Taka-ishi N. Tamura I. Fujii H. J. Org. Chem.  1969,  34:  1145 
• 9 Northrop RC. Russ PL. J. Org. Chem.  1975,  40:  558 
• 10 Wanzlick HW. Lochel W. Chem. Ber.  1963,  86:  1463 
• 11 Katritzky AR. Suzuki K. He HY. J. Org. Chem.  2002,  67:  3109 
• 12a 1,3-Dipolar Cycloaddition Chemistry   Vol. 1:  Padwa A. Wiley; New York: 1984. 
• 12b 1,3-Dipolar Cycloaddition Chemistry   Vol. 2:  Padwa A. Wiley; New York: 1984. 
• 12c Pandey G. Banerjee P. Gadre SR. Chem. Rev.  2006,  106:  4484 
• 13 Grigg R. Sridharan V. In Advances in Cycloaddition   Vol. 3:  Curran DP. Jai Press; London: 1993.  p.161 
• 14a Suresh Babu AR. Raghunathan R. Tetrahedron Lett.  2007,  48:  6809 
• 14b Subramaniyan G. Raghunathan R. Martin Castro AM. Synthesis  2002,  2440 
• 14c Jayashankaran J. Rathna Durga RSM. Raghunathan R. Tetrahedron Lett.  2004,  45:  7303 
• 14d Suresh Babu AR. Raghunathan R. Tetrahedron Lett.  2008,  49:  4487 
• 17 Arumugam N. Raghunathan R. Tetrahedron Lett.  2006,  47:  8855 
• 18a Simon A. Simon C. Kanda T. Nagashima S. Mitoma T. Yamada T. Mimura K. Tashiro M. J. Chem. Soc., Perkin Trans. 1  2001,  2071 
• 18b Armstrong LG. Lindoy LF. Inorg. Chem.  1975,  14:  1322 

15

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%).

16

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.

19

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.

20

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.

21

Macrocyclic Imidazolidine 6: R_f = 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.

22

Macrocyclic Imidazolidine 10a: R_f = 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.

23

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.