Synlett 2013; 24(19): 2540-2544
DOI: 10.1055/s-0033-1339876
cluster
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Highly Basic Hexasubstituted Biguanides by Environmentally Friendly Methods

Zoran Glasovac
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia   Fax: +385(1)4561008   Email: margetid@irb.hr   Email: mmaksic@emma.irb.hr
,
Pavle Trošelj
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia   Fax: +385(1)4561008   Email: margetid@irb.hr   Email: mmaksic@emma.irb.hr
,
Iva Jušinski
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia   Fax: +385(1)4561008   Email: margetid@irb.hr   Email: mmaksic@emma.irb.hr
,
Davor Margetić*
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia   Fax: +385(1)4561008   Email: margetid@irb.hr   Email: mmaksic@emma.irb.hr
,
Mirjana Eckert-Maksić*
Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia   Fax: +385(1)4561008   Email: margetid@irb.hr   Email: mmaksic@emma.irb.hr
› Author Affiliations
Further Information

Publication History

Received: 29 July 2013

Accepted: 05 September 2013

Publication Date:
14 October 2013 (online)


Abstract

A series of hexasubstituted biguanides was synthetized employing nonconventional and environmentally friendly methods. Their properties were studied computationally (basicity) and experimentally (basicity and catalytic properties in transesterification reaction).

Supporting Information

 
  • References and Notes

  • 1 Margetić D In Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts Ishikawa T. Wiley; Chichester: 2009. Chap. 9, 4
  • 2 Ishikawa T, Isobe T. Chem. Eur. J. 2003; 8: 552
  • 4 Gelbard G, Vielfaure-Joly F. Tetrahedron Lett. 1998; 39: 2743
    • 5a Margetić D, Ishikawa T, Kumamoto T. Eur. J. Org. Chem. 2010; 6563
    • 5b Margetić D, Trošelj P, Ishikawa T, Kumamoto T. Bull. Chem. Soc. Jpn. 2010; 83: 1055
  • 6 Maksić ZB, Kovačević B, Vianello R. Chem. Rev. 2012; 112: 5240
  • 7 Maksić ZB, Kovačević B. J. Org. Chem. 2000; 65: 3303
    • 8a Kovačević B, Glasovac Z, Maksić ZB. J. Phys. Org. Chem. 2002; 15: 765
    • 8b Eckert-Maksić M, Glasovac Z, Trošelj P, Kütt A, Rodima T, Koppel I, Koppel IA. Eur. J. Org. Chem. 2008; 5176
    • 8c Glasovac Z, Štrukil V, Eckert-Maksić M, Schroeder D, Kaczorowska M, Schwarz H. Int. J. Mass Spectrom. 2008; 270: 39
    • 8d Glasovac Z, Pavošević F, Štrukil V, Eckert-Maksić M, Schlangen M, Kretschmer R. Int. J. Mass Spectrom. 2013; in press
  • 9 Biguanides 3a and 3b are known compounds, see ref. 4.
  • 10 General Procedures Microwave Reaction The reactants were mixed in the nitrogen-flushed cuvette in the ratio 1/2 = 1:1.3 on the 2 mmol scale. The cuvette was heated under microwave irradiation for the desired reaction time (see Tables 1 and S1). Formed biguanides were isolated according to the procedure given below. High-Speed Vibrational Milling Reaction Reactants were mixed in a stainless steel jar and milled under conditions given in Tables 1 or S1. After milling for the desired period of time, CH2Cl2 was added, and the product mixture was filtered over Celite and charcoal and washed with CH2Cl2. Filtrate was evaporated to dryness, and the product was isolated as described below. High-Pressure Reaction The mixture of reactants in a molar ratio of 1/2 = 1:1.3 on the 1 mmol scale in the closed Teflon reaction vessel was subjected to the pressure of 6–8 kbar. After 24 h reaction the mixture was transferred into the flask, and the conversion was analyzed by GC. Ultrasound Reaction The reaction mixture was prepared in the same way as for the microwave-assisted reaction. The cuvette was immersed in the water bath preheated to 50 °C and agitated using ultrasound. Conversion of the carbodiimides into the products was determined by GC. Thermal Reaction The solution of reactants in dry THF (1 mL) was prepared in a microwave cuvette, closed, and immersed in an oil bath preheated to 90 °C. The progress of the reaction was followed by GC analysis after 1 or 2 h. The reaction mixture was then cooled, and the product was isolated as described below. Isolation of the Products The crude reaction mixture was transferred into the reaction flask, and the excess of 1 was removed via bulb-to-bulb distillation under reduced pressure. The obtained viscous material was dissolved in CH2Cl2 (7 mL) and washed with H2O. The crude product was obtained either by evaporation of the water (3be) or dichloromethane layer (3a, 3f, and 3g). Biguanide 3b was washed 7 times with 10 mL of H2O until complete transfer into the water layer was achieved. In other cases, 3 × 7 mL H2O portions were sufficient for the extractions. The hydrochloride salt of 3c was deprotonated by dissolving the crude salt in dry MeOH (10 mL) containing NaOH (1 mol equiv). The solution was stirred for 30 min at r.t. and evaporated to dryness. The remaining material was mulled in CH2Cl2, and the solid was collected by filtration. The filtrate was evaporated to dryness and subjected to vacuum distillation. Biguanides 3ae were further purified by vacuum distillation at 2–5·10–5 mbar (10–3 Pa) at the oil bath temperature of 150–180 °C.
  • 11 New compounds gave satisfactory physical and spectral data (1H NMR, 13C NMR, and HRMS spectra). Selected Physical and Spectral Data Compound 3c: colorless viscous oil. 1H NMR (600 MHz, CD3CN): δ = 1.06 (t, J = 7.2 Hz, 3 H), 1.59 (q, J = 7.1 Hz, 2 H), 2.16 (s, 6 H), 2.27 (t, J = 7.2 Hz, 2 H), 2.73 (s, 12 H), 2.90–3.00 (m, 4 H). 13C NMR (150 MHz, CD3CN): δ = 16.4, 29.5, 38.9, 39.3, 43.2, 45.4, 58.6, 156.2, 159.9. Compound 3d: colorless viscous oil. 1H NMR (300 MHz, DMSO-d6): δ = 1.58 (q, J = 6.9 Hz, 2 H), 2.11 (s, 12 H), 2.23 (t, J = 7.0 Hz, 2 H), 2.75 (s, 12 H), 2.98 (t, J = 6.7 Hz, 2 H). 13C NMR (75 MHz, DMSO-d6): δ = 27.8, 39.6, 45.6, 49.0, 57.3, 157.7, 161.6. Compound 3e: colorless viscous oil. 1H NMR (600 MHz, CD3CN): δ = 1.71 (q, J = 6.5 Hz, 4 H), 2.74 (s, 12 H), 2.99 (t, J = 6.5 Hz, 4 H), 3.32 (s, 6 H), 3.42 (t, J = 6.5 Hz, 4 H). 13C NMR (150 MHz, DMSO-d6): δ = 31.1, 39.1, 49.0, 58.2, 71.1, 156.0, 159.0. Compound 3f: brownish-yellow viscous oil. 1H NMR (600 MHz, CDCl3): δ = 1.74 (q, J = 7.0 Hz, 2 H), 2.20 (s, 6 H), 2.33 (t, J = 7.0 Hz, 2 H), 2.50 (s, 12 H), 3.31 (t, J = 7.0 Hz, 2 H), 3.71 (s, 3 H), 6.68 (d, J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85 Hz, 2 H). 13C NMR (150 MHz, CDCl3): δ = 27.8, 38.6, 40.6, 45.6, 57.9, 120.3, 122.7, 128.1, 150.2, 155.7, 160.7. Compound 3g: brownish-yellow viscous oil. 1H NMR (600 MHz, CDCl3): δ = 1.74 (q, J = 7.0 Hz, 2 H), 2.20 (s, 6 H), 2.33 (t, J = 7.0 Hz, 2 H), 2.50 (s, 12 H), 3.31 (t, J = 7.0 Hz, 2 H), 3.71 (s, 3 H), 6.68 (d, J = 8.85 Hz, 2 H), 6.75 (d, J = 8.85 Hz, 2 H). 13C NMR (150 MHz, CDCl3): δ = 27.8, 38.7, 40.6, 45.5, 55.6, 57.9, 113.6, 123.4, 128.2, 154.0, 155.8, 160.4. For further details see Supporting Information.
  • 12 Margetić D. Microwave Assisted Cycloaddition Reactions. Nova Science Publishers; New York: 2011
    • 13a Margetić D. Kem. Ind. 2005; 54: 351
    • 13b Štrukil V, Margetić D, Igrc MD, Eckert-Maksić M, Friščić T. Chem. Commun. 2012; 48: 9705
    • 13c Štrukil V, Igrc MD, Fábián L, Eckert-Maksić M, Childs SL, Reid DG, Duer MJ, Halasz I, Mottillo C, Friščić T. Green Chem. 2012; 14: 2462
  • 14 Organic Synthesis at High Pressures. Matsumoto K, Acheson RM. Wiley; New York: 1991
  • 15 Luche JL. Synthetic Organic Sonochemistry. Plenum Press; New York: 1998
  • 16 Mayer S, Daigle DM, Brown ED, Khatri J, Organ MG. J. Comb. Chem. 2004; 6: 776
  • 17 Control of the temperature is critical and overheating must be avoided – the temperature was not allowed to rise above 90 °C.
  • 18 Glasovac Z, Eckert-Maksić M, Maksić ZB. New J. Chem. 2009; 33: 588
  • 19 Štrukil V, Glasovac Z, Đilović I, Matković-Čalogović D, Šuman L, Kralj M, Eckert-Maksić M. Eur. J. Org. Chem. 2012; 6758
  • 20 Kaljurand I, Kütt A, Sooväli L, Rodima T, Mäemets V, Leito I, Koppel IA. J. Org. Chem. 2005; 70: 1019
  • 21 See: Raab V, Gautchenova K, Merkoulov A, Harms K, Sundermayer J, Kovačević B, Maksić ZB. J. Am. Chem. Soc. 2005; 127: 17656
  • 22 Schuchardt U, Vargas RM, Gelbard G. J. Mol. Catal. A: Chem. 1995; 99: 65 ; the experimental setup was modified with respect to the original paper (see Supporting Information)
  • 23 Substitution numbering (Figure 2).