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

<A NAME="RD04907ST-1A">1a</A> Attanasi OA. Caglioti L. Org. Prep. Proced. Int.  1986,  18:  299 

<A NAME="RD04907ST-1B">1b</A> Attanasi OA. Filippone P. Synlett  1997,  1128 

<A NAME="RD04907ST-1C">1c</A> Boeckman RK. Reed J. Ge P. Org. Lett.  2001,  3:  3651 

<A NAME="RD04907ST-1D">1d</A> Avalos M. Babiano R. Cintas P. Clemente FR. Gordillo R. Jiménez JL. Palacios JC. J. Org. Chem.  2002,  67:  2241 

<A NAME="RD04907ST-1E">1e</A> Palacios F. Aparicio D. de los Santos JM. Tetrahedron  1999,  55:  13767 

<A NAME="RD04907ST-2A">2a</A> Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 ; and the references cited therein

<A NAME="RD04907ST-2B">2b</A> Attanasi OA. Filippone P. Perrulli FR. Santeusanio S. Eur. J. Org. Chem.  2002,  2323 

<A NAME="RD04907ST-2C">2c</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Mantellini F. Santeusanio S. Synlett  2004,  549 

<A NAME="RD04907ST-2D">2d</A> Attanasi OA. Carvoli G. Filippone P. Perrulli FR. Santeusanio S. Serri AM. Synlett  2004,  1643 

<A NAME="RD04907ST-2E">2e</A> Attanasi OA. De Crescentini L. Favi G. Filippone P. Lillini S. Mantellini F. Santeusanio S. Synlett  2005,  1474 

<A NAME="RD04907ST-2F">2f</A> Attanasi OA. Baccolini G. Boga C. De Crescentini L. Filippone P. Mantellini F. J. Org. Chem.  2005,  70:  4033 

<A NAME="RD04907ST-2G">2g</A> Attanasi OA. Favi G. Filippone P. Giorgi G. Lillini S. Mantellini F. Perrulli FR. Synlett  2006,  2731 

<A NAME="RD04907ST-3">3</A> Grimmet MR. Imidazoles In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; London: 1996. 

<A NAME="RD04907ST-4A">4a</A> Du H. He Y. Rasapalli S. Lovely CJ. Synlett  2006,  965 

<A NAME="RD04907ST-4B">4b</A> Jin Z. Nat. Prod. Rep.  2005,  22:  196 

<A NAME="RD04907ST-4C">4c</A> Hoffmann H. Lindel T. Synthesis  2003,  1753 

<A NAME="RD04907ST-5A">5a</A> De Luca L. Curr. Med. Chem.  2006,  13:  1 

<A NAME="RD04907ST-5B">5b</A> Gross H. Kehraus S. Koenig GM. Woerheide G. Wright AD. J. Nat. Prod.  2002,  65:  1190 

<A NAME="RD04907ST-6A">6a</A> 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 

<A NAME="RD04907ST-6B">6b</A> 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 

<A NAME="RD04907ST-6C">6c</A> 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 

<A NAME="RD04907ST-7">7</A>

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).

<A NAME="RD04907ST-8">8</A>

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.

<A NAME="RD04907ST-9A">9a</A> Attanasi OA. Filippone P. De Crescentini L. Foresti E. Galarini R. Santeusanio S. Serra-Zanetti F. Synthesis  1995,  1397 

<A NAME="RD04907ST-9B">9b</A> Attanasi OA. Filippone P. Foresti E. Guidi B. Santeusanio S. Tetrahedron  1999,  55:  13423 

<A NAME="RD04907ST-10">10</A>

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).

<A NAME="RD04907ST-11">11</A>

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]].

<A NAME="RD04907ST-12">12</A>

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).

<A NAME="RD04907ST-13">13</A>

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.

<A NAME="RD04907ST-14A">14a</A> Brackeen MF. Stafford JA. Feldman PL. Karanewsky DS. Tetrahedron Lett.  1994,  1635 

<A NAME="RD04907ST-14B">14b</A> Zhang PF. Chen ZC. Synthesis  2001,  2075 

<A NAME="RD04907ST-14C">14c</A> Yoburn JC. Baskaran S. Org. Lett.  2005,  7:  3801 

<A NAME="RD04907ST-15">15</A> 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 

<A NAME="RD04907ST-16">16</A> 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 

<A NAME="RD04907ST-17">17</A> Street JP. Tetrahedron Lett.  1991,  32:  3333