Download PDF
Synlett 2011(3): 315-318  
DOI: 10.1055/s-0030-1259299
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A One-Pot Preparation of 5-Oxo 2,4-Disubstituted 2,5-Dihydro-1H-imidazol-2-carboxylates from α-Bromo Esters

Dariusz Cież*a, Jan Svetlikb
a Department of Organic Chemistry, Jagiellonian University, 30060 Kraków, Poland
Fax: +48(12)6340515; e-Mail: ciez@chemia.uj.edu.pl;
b Department of Pharmaceutical Analysis and Nuclear Pharmacy, Comenius University, 83232 Bratislava, Slovak Republic
Further Information

Publication History

Received 11 October 2010
Publication Date:
05 January 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

Nucleophilic substitution of a bromine atom by the azide group in aryl- and heteroaryl-α-bromoacetates triggers cascade reactions leading to imidazolin-5-ones formation. The α-azidoacetate intermediates undergo a transformation into non-isolable 2-imino esters that dimerize giving the heterocyclic imidazoline system. The process described is strongly promoted by dipolar aprotic solvents (DMF, DMSO) and could be realized under base- and metal-free conditions.

Key words

azides - cyclization - substitution - imidazolin-5-ones - nitrenes

    References and Notes

  • 1 Pandya KC. Kurien PN. Surange VR. J. Indian Chem. Soc.  1934,  11:  823 
    Google Scholar
  • 2 Wright WB. Brabander HJ. Hardy RA. Osterberg AC. J. Med. Chem.  1966,  9:  852 
    CrossrefGoogle Scholar
  • 3 Goldberg MW, and Lehr HH. inventors; US Patent,  US2602086. 
  • 4 Karjalainen AJ, Kurkela K, Oiva APS, and Sulevi L. inventors; Eur. Patent  EP0058047. 
  • 5 Kumar P. Nath C. Shanker K. Pharmazie  1985,  40:  267 
    Google Scholar
  • 6a Khan KM. Mughal UR. Samreen NA. J. Enzyme Inhib. Med. Ch.  2010,  25:  29 
    Google Scholar
  • 6b Amir M. Kumar A. Ali I. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  2009,  48:  1288 
    Google Scholar
  • 6c Desai NC. Bhavsar AM. Baldaniya BB. Indian J. Pharm. Sci.  2009,  71:  90 
    Google Scholar
  • 7 Zhou P. Malamas M. Robichaud AJ. ARKIVOC  2010,  (vi):  84 
    Google Scholar
  • 8 Jain V. Bhattacharjya G. Tej A. Suman CK. Gurunath R. Mazhari B. Iyer SSK. Proceedings of ASID ’06   IITK & SID; New Delhi: 2006.  8-12 Oct. p.244 
    Google Scholar
  • 9 Bahadur L. Roy L. J. Appl. Electrochem.  1999,  29:  109 
    CrossrefGoogle Scholar
  • 10a Mukerjee AK. Kumar P. Can. J. Chem.  1982,  60:  317 
    Google Scholar
  • 10b Kelarev VI. Silin MA. Borisova OA. Chem. Heterocycl. Compd.  2003,  39:  729 
    Google Scholar
  • 10c Hamidian H. Tikdari AM. Khabazzadeh H. Molecules  2006,  11:  377 
    Google Scholar
  • 10d Wadekar MP. Raut AR. Murhekar GH. Der Pharma Chemica  2010,  2(1):  76 
    Google Scholar
  • 11a Kawasaki A. Maekawa K. Kubo K. Igarashi T. Sakurai T. Tetrahedron  2004,  60:  9517 
    Google Scholar
  • 11b Topuzyan VO. Arutyunyan LG. Oganesyan AA. Panosyan GA. Russ. J. Org. Chem.  2007,  43:  936 
    Google Scholar
  • 11c Topuzyan VO. Arutyunyan LG. Oganesyan AA. Panosyan GA. Russ. J. Org. Chem.  2008,  44:  474 
    Google Scholar
  • 13a Cież D. Org. Lett.  2009,  11:  4282 
    Google Scholar
  • 13b For more data on instability of lithium enolates of α-azidocarboxylic esters, see also: Manis PA. Rathke MW. J. Org. Chem.  1980,  45:  4952 
    Google Scholar
  • 14a Matsuda Y. Tanimoto S. Okamoto T. Ali SM.
    J. Chem. Soc., Perkin Trans. 1  1989,  279 
    Google Scholar
  • 14b Yasunobu A. Shoko T. Tomomi K. Masanori S. Chem. Pharm. Bull.  1984,  32:  1800 
    Google Scholar
  • 15 Paul A. Bittermann H. Gmeiner P. Tetrahedron  2006,  62:  8919 
    CrossrefGoogle Scholar
  • 18a Bock H. Dammel R. Horner L. Chem. Ber.  1981,  114:  220 
    Google Scholar
  • 18b Bock H. Dammel RS. Aygen J. J. Am. Chem. Soc.  1983,  105:  7681 
    Google Scholar
  • 18c Bock H. Dammel R. Angew. Chem., Int. Ed. Engl.  1987,  26:  504 ; Angew. Chem. 1987, 99, 518
    Google Scholar
  • 18d Bock H. Dammel R. J. Am. Chem. Soc.  1988,  110:  5261 
    Google Scholar
  • For more details, see:
  • 19a Dyke JM. Levita G. Morris AJ. Ogden S. Dias AA. Algarra M. Santos JP. Costa ML. Rodrigues P. Andrade MM. Barros MT. Chem. Eur. J.  2005,  11:  1665 
    Google Scholar
  • 19b Shirtcliff LD. McClintock SP. Haley MM. Chem. Soc. Rev.  2008,  37:  343 
    Google Scholar
  • 19c Trost BM. Fleming I. Ley SV. Oxidation   In Comprehensive Organic Synthesis - Selectivity, Strategy and Efficiency in Modern Organic Chemistry   Vol. 7: 5th ed.:  Elsevier Ltd.; Amsterdam: 2005.  p.23 
    Google Scholar
  • 20a Poisel H. Chem. Ber.  1977,  110:  942 
    Google Scholar
  • 20b Shin C. Masaki M. Ohta M. Bull. Chem. Soc. Jpn.  1971,  44:  1657 
    Google Scholar
12

¹H NMR (600 MHz, DMSO-d 6): δ = 11.25 (s, 1 H, NH), 8.38 (d, 2 H, J HH = 7.8 Hz, CHAr), 7.62 (m, 2 H, CHAr), 7.54 (t, 2 H, J HH = 7.8 Hz, CHAr), 7.44 (t, 2 H, J HH = 7.8 Hz, CHAr), 7.40 (t, 2 H, J HH = 7.2 Hz, CHAr), 4.17 (q, 2 H, J HH = 7.2 Hz, CH3CH 2O), 1.14 (t, 3 H, J HH = 7.2 Hz, CH 3CH2O). ¹³C NMR (150 MHz, DMSO-d 6): δ = 167.7, 164.8, 162.9, 137.3, 132.3, 129.6, 128.8, 128.7, 128.4, 128.3, 126.5, 86.5, 62.5, 13.8. All 2D NMR experiments for 3a were carried out using DMSO-d 6 as a solvent. COSY correlation list: δ [ppm]-δ [ppm](assignment): 1.14-4.17 (CH 3CH2O), 4.17-1.14 (CH3CH 2O), 7.40-7.44 (p-CH), 7.44-7.40, 7.62 (m-CH), 7.54-7.62, 8.38 (m-CH), 7.62-7.54 (p-CH), 7.62-7.44 (o-CH), 8.38-7.54 (o-CH). HSQC: correlation list: ¹³C shift [ppm]-¹H shift [ppm](assignment): 13.7-1.14 (CH 3CH2O), 62.5-4.17 (CH3 CH 2O), 126.5-7.62 (o-CH), 128.3-8.38 (o-CH), 128.4-7.44 (m-CH), 128.7-7.54 (m-CH), 128.8-7.40 (p-CH), 132.3-7.62 (p-CH). HMBC: correlation list: ¹H shift [ppm]-¹³C shifts [ppm] (atom connectivity): 1.14-62.5 (ester group CH 3 CH2O), 4.17-13.7 and 167.7 (ester group CH3CH 2OCO), 7.40-126.5 (p-CH and C-2, phenyl group A), 7.44-126.5, 128.8 and 137.4 (m-CH and C-2, C-4, C-1, phenyl group A), 7.54-128.3, 129.6 (m-CH and C-2, C-1, phenyl group B), 7.62-86.9, 126.5 and 128.8 (o-CH and quaternary C-2 of the imidazolidine ring, C-2, C-4, phenyl group A), 7.62-128.3 (p-CH and C-2, phenyl group B), 8.38-128.7, 132.3 and 162.9 (o-CH and C-3, C-4 in phenyl group B and C=N in the imidazolidine ring), 11.25-86.9, 162.9 and 164.8 (NH group and quaternary C-2, C=N and C=O in the imidazolidine ring). According to HMBC data, phenyl substituents A and B were attached to the imidazolidine ring at C-2 and C-4, respectively.

16

General Method for Preparation of Imidazolin-5-ones 3 from α-Bromoacetates; Representative One-Pot Synthesis of Ethyl 2,4-Bis(4-ethoxyphenyl)-5-oxo-2,5-dihydro-1 H -imidazole-2-carboxylate (3d): Ethyl α-bromo-2-(4-ethoxyphenylacetate) (4d; 1.254 g, 4.4 mmol) and sodium azide (0.428 g, 6.6 mmol, 1.5 equiv) were added to DMF (20 mL). The suspension was stirred and heated for 24 h at 80 ˚C. After cooling, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (3 × 30 mL). The combined extracts were washed with H2O (2 × 50 mL) and dried over anhyd Na2SO4. The mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using silica gel (230-400 mesh; CHCl3-MeOH, 30:1) to give 3d as colorless crystals (TLC silica gel; Fluka 60778; CHCl3-MeOH, 30:1; R f 0.55); mp 132 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 8.48 (d, 2 H, J HH = 9.1 Hz, CHAr), 8.40 (br s, 1 H, NH), 7.50 (d, 2 H, J HH = 9.0 Hz, CHAr), 6.95 (d, 2 H, J HH = 9.1 Hz, CHAr), 6.89 (d, 2 H, J HH = 9.0 Hz, CHAr), 4.25 (2 × dq, 2 H, J HH = 7.11, 7.14, 10.7 Hz, OCH2), 4.10 (q, 2 H, J HH = 7.0 Hz, OCH2), 4.02 (q, 2 H, J HH = 7.0 Hz, OCH2), 1.44 (t, 3 H, J HH = 7.0 Hz, Me), 1.40 (t, 3 H, J HH = 7.0 Hz, Me), 1.26 (t, 3 H, J HH = 7.1 Hz, Me). ¹³C NMR (75 MHz, CDCl3): δ = 168.3 (COOEt), 165.7 (CONH), 162.3 (C=N), 161.6 (C4), 159.5 (C4), 130.8 (C3), 129.0 (C1), 127.4 (C3), 122.3 (C1), 114.6 (C2), 114.4 (C2), 86.0 (C2-imidazolidine), 63.6 (OCH2), 63.5 (OCH2), 62.9 (OCH2), 14.7 (Me), 14.7 (Me), 14.0 (Me). IR (neat): 3168, 3071, 2979, 2936, 1742, 1705, 1595, 1571, 1512, 1237, 1172 cm-¹. Anal. Calcd for C22H24N2O5: C, 66.65; H, 6.10; N, 7.06. Found: C, 66.45; H, 6.01; N, 7.10.

17

Standard Procedure for Synthesis of α-Bromoacetates from Commercial Ethyl Aryl- and Heteroarylacetates; Representative Preparation of Ethyl Bromo(4-ethoxy-phenyl) Acetate (4d): Ethyl 4-ethoxyphenylacetate (1.695 g, 8.14 mmol) was treated with NBS (1.449 g, 1 equiv) and Luperox® A70S (0.176 g, 0.50 mmol) in CCl4 (30 mL). The reaction mixture was stirred and heated for 30 h at 74 ˚C. After cooling the solution was filtered through a Celite pad and the solvent was evaporated. The crude product, ethyl bromo(4-ethoxyphenyl) acetate (4d), was pure enough to be used for the next step.

21

Partial NMR data for diethyl iminomalonate were determined from the crude reaction mixture. ¹H NMR (300 MHz, CDCl3): δ = 11.76 (br s, 1 H, NH), 4.29 (q, 2 H, J HH = 7.1 Hz, OCH2), 1.30 (t, 3 H, J HH = 7.1 Hz, Me). ¹³C NMR (75 MHz, CDCl3): δ = 161.0 (COOEt), 152.3 (C=NH), 61.6 (OCH2), 14.3 (Me).