One-Pot Synthesis of Spiro Pyrroloimidazoles and 2-Arylimidazoles from 1,2-Diaza-1,3-butadienes and Arylamidines

Abstract

1,2-Diaza-1,3-butadienes react as Michael acceptors with nitrogen 1,3-dinucleophiles, such as arylamidines, in a one-pot heterocyclization reaction. Depending on the nature of the acyl ­residue at the terminal carbon of the heterodiene system, spiro ­pyrroloimidazole derivatives or 2-arylimidazoles can be obtained.

1,2-diaza-1,3-butadienes - arylamidines - nucleophilic additions - cyclizations - spiro compounds

References and Notes

1a Attanasi OA. Caglioti L. Org. Prep. Proced. Int.  1986,  18:  299 

1b Attanasi OA. Filippone P. Synlett  1997,  1128 

1c Boeckman RK. Reed J. Ge P. Org. Lett.  2001,  3:  3651 

1d Avalos M. Babiano R. Cintas P. Clemente FR. Gordillo R. Jiménez JL. Palacios JC. J. Org. Chem.  2002,  67:  2241 

1e Palacios F. Aparicio D. de los Santos JM. Tetrahedron  1999,  55:  13767 

2a Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 ; and the references cited therein

2b Attanasi OA. Filippone P. Perrulli FR. Santeusanio S. Eur. J. Org. Chem.  2002,  2323 

2c Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. Synlett  2004,  549 

2d Attanasi OA. Carvoli G. Filippone P. Perrulli FR. Santeusanio S. Serri AM. Synlett  2004,  1643 

2e Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Synlett  2005,  1474 

2f Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem.  2005,  70:  4033 

2g Attanasi OA. Favi G. Filippone P. Giorgi G. Lillini S. Mantellini F. Perrulli FR. Synlett  2006,  2731 

3 Grimmet MR. Imidazoles In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; London: 1996. 

4a Du H. He Y. Rasapalli S. Lovely CJ. Synlett  2006,  965 

4b Jin Z. Nat. Prod. Rep.  2005,  22:  196 

4c Hoffmann H. Lindel T. Synthesis  2003,  1753 

5a De Luca L. Curr. Med. Chem.  2006,  13:  1 

5b Gross H. Kehraus S. Koenig GM. Woerheide G. Wright AD. J. Nat. Prod.  2002,  65:  1190 

6a Khanna I. Weir RM. Xiang YY. Xu XD. Koszyk FJ. Collins PW. Kobolt CM. Veenhuinzen AW. Perkin WE. Casler JJ. Masferrer JL. Zhang YY. Gregory SA. Seibert K. Isakson PC. J. Med. Chem.  1997,  40:  1634 

6b Yanagisawa H. Amemiya Y. Kanasaki T. Shimoji Y. Fujimoto K. Kitahara Y. Sada T. Mizuno M. Ikeda M. Miyamoto S. Furukawa Y. Koibe H. J. Med. Chem.  1996,  39:  323 

6c Carini D. Duncia JV. Aldrich PE. Chiu AT. Johnson AL. Pierce ME. Price WA. Santella JB. Wells GJ. Wexler RR. J. Med. Chem.  1991,  34:  2525 

7

Procedure for the Preparation of Spiro Pyrroloimidazole Derivatives 3a-i 1,2-Diaza-1,3-butadiene 1a-e (2 mmol), prepared and used as a EE/EZ-isomer mixture,^1b and DIPEA (2 mmol) were dissolved in THF (8 mL) under magnetic stirring. Then solid arylamidine 2a,b (1 mmol) was added and the reaction mixture was allowed to stand at r.t. until complete disappearance of 1a-e (0.25-1 h, monitored by silica gel TLC). The reaction mixture was then refluxed for the appropriate time (4-6 h). The solvent was removed under reduced pressure and the diastereomers of 3a-i were obtained by silica gel chromatographic separation (eluent: CH₂Cl₂-EtOAc mixtures).

8

Data for Methyl 7-[(Methoxycarbonyl)amino]-6-[2-(methoxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-2-phenyl-1,3,7-triazaspiro[4.4]nona-1,8-diene-9-carboxylate (3b)
5 R / S ,6 R / S-Isomer
White powder from EtOAc-n-pentane, mp 161-163 °C (dec.). IR (Nujol): 3465, 3303, 3244, 3192, 1735, 1721, 1707, 1673, 1648, 1608, 1543, 1515 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.06 (s, 3 H, CH₃), 2.10 (s, 3 H, CH₃), 3.46 (s, 3 H, OCH₃), 3.60 (s, 3 H, OCH₃), 3.69 (s, 3 H, OCH₃), 6.13 (s, 1 H, NH), 7.53 (t, J = 7.6 Hz, 2 H, Ar), 7.60 (t, J = 7.6 Hz, 1 H, Ar), 7.98 (d, J = 7.6 Hz, 2 H, Ar), 8.27 (s, 1 H, NH), 8.81 (s, 1 H, NH), 11.88 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.58, 16.47, 50.31, 52.34, 81.45, 88.87, 96.90, 126.86, 128.37, 128.78, 131.82, 156.29, 156.95, 158.41, 163.86, 184.58. MS: m/z (%) = 460 [M⁺] (4), 370 (100), 296 (22), 236 (42). Anal. Calcd for C₂₀H₂₄N₆O₇: C, 52.17; H, 5.25; N, 18.25. Found: C, 52.20; H, 5.22; N, 18.27.
5 R / S ,6 S / R -Isomer
Colorless crystals from THF-n-pentane, mp 152-154 °C (dec.). IR (Nujol): 3484, 3435, 3339, 3306, 1744, 1723, 1687, 1620, 1602, 1578, 1511 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.15 (s, 3 H, CH₃), 2.11 (s, 3 H, CH₃), 3.42 (s, 3 H, OCH₃), 3.60 (s, 3 H, OCH₃), 3.68 (s, 3 H, OCH₃), 5.90 (s, 1 H, NH), 7.56 (t, J = 7.6 Hz, 2 H, Ar), 7.62 (t, J = 7.6 Hz, 1 H, Ar), 7.90 (s, 1 H, NH), 8.04 (d, J = 7.6 Hz, 2 H, Ar), 8.64 (s, 1 H, NH), 11.65 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.86, 17.06, 50.31, 52.31, 52.46, 80.22, 85.91, 96.72, 127.37, 128.35, 128.75, 132.18, 156.46, 156.54, 161.88, 163.64, 164.18, 183.08. MS: m/z (%) = 460 [M⁺] (1), 370 (100), 296 (21), 236 (18). Anal. Calcd for C₂₀H₂₄N₆O₇: C, 52.17; H, 5.25; N, 18.25. Found: C, 52.16; H, 5.23; N, 18.26.

9a Attanasi OA. Filippone P. De Crescentini L. Foresti E. Galarini R. Santeusanio S. Serra-Zanetti F. Synthesis  1995,  1397 

9b Attanasi OA. Filippone P. Foresti E. Guidi B. Santeusanio S. Tetrahedron  1999,  55:  13423 

10

Data of B": ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.39 (s, 9 H, Ot-Bu), 1.94 (s, 3 H, CH₃), 6.86 (s, 1 H, NH), 7.54 (t, J = 7.6 Hz, 2 H, Ar), 7.61 (t, J = 7.6 Hz, 1 H, Ar), 7.95 (d, J = 7.6 Hz, 2 H, Ar), 9.64 (s, 1 H, NH), 11.41 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.99, 27.97, 79.19, 93.64, 127.09, 128.38, 128.76, 132.26, 151.66, 152.66, 160.86, 181.69. MS: m/z (%) = 317 [M⁺ + 1] (0.5), 260 (3), 216 (12), 202 (57), 104 (100).

11

Crystallographic data (excluding structure factors) for compound 3b and 4c have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 637246 and 637245. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

12

Procedure for the Preparation 2-Arylimidazole Derivatives 4a-e To a solution of 1,2-diaza-1,3-butadiene 1f-i (1 mmol) and DIEA (1.2 mmol) in THF (6 mL) solid arylamidine 2a,b (1 mmol) was added under magnetic stirring at r.t. After the disappearance of 1f-i (0.25-0.5 h) the reaction mixture was refluxed (4-6 h). Compound 4a was obtained by direct crystallization from the reaction medium and was filtered off with satisfactory purity whereas compounds 4b-e were obtained after chromatographic purification (elution: CH₂Cl₂-EtOAc mixtures).

13

Data for N , N -Diethyl-5-methyl-2-phenyl-1 H -imidazole-4-carboxamide (4c)
Colorless crystals from Et₂O, mp 187-190 °C. IR (Nujol): 3114, 1595,1566, 1538, 1494 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.14 (br s, 3 H, CH₃), 1.23 (br s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 3.37 (br s, 2 H, NCH₂), 3.77 (br s, 2 H, NCH₂), 7.34 (t, J = 7.6 Hz, 1 H, Ar), 7.45 (t, J = 7.6 Hz, 2 H, Ar), 7.90 (d, J = 7.6 Hz, 2 H, Ar), 12.59 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 10.84, 12.97, 14.68, 39.66, 42.45, 124.59, 128.01, 128.70, 130.33, 132.54, 132.76, 142.21, 164.12. MS: m/z (%) = 257 [M⁺] (27), 185 (100), 158 (99). Anal. Calcd for C₁₅H₁₉N₃O: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.99; H, 7.47; N, 16.35.

14a Brackeen MF. Stafford JA. Feldman PL. Karanewsky DS. Tetrahedron Lett.  1994,  1635 

14b Zhang PF. Chen ZC. Synthesis  2001,  2075 

14c Yoburn JC. Baskaran S. Org. Lett.  2005,  7:  3801 

15 Bartroli J. Turmo E. Alguero M. Boncompte E. Vericat ML. Conte L. Ramis J. Merlos M. Garcia-Rafanell J. Forn J. J. Med. Chem.  1998,  41:  1855 

16 Elliott RL. Oliver RM. LaFlamme JA. Gillaspy ML. Hammond M. Hank RF. Maurer TS. Baker DL. DaSilva-Jardine PA. Stevenson RW. Mack CM. Cassella JV. Bioorg. Med. Chem. Lett.  2003,  13:  3593 

17 Street JP. Tetrahedron Lett.  1991,  32:  3333