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Synlett 2010(1): 85-88  
DOI: 10.1055/s-0029-1218553
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Novel Isochromene Derivatives by Tandem Ugi Reaction/Nucleophilic Substitution

Luca Banfi*a, Andrea Bassoa, Francesco Casuscellib, Giuseppe Guantia, Farah Naza, Renata Rivaa, Paola Zitoa
a Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova, Italy
Fax: +39(010)3536118; e-Mail: banfi@chimica.unige.it;
b Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano (MI), Italy
Further Information

Publication History

Received 23 October 2009
Publication Date:
09 December 2009 (online)

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Abstract

Unprecedented 3-amino-4-amido-1H-isochromenes have been prepared in three steps from protected ortho-(hydroxy­methyl)benzaldehyde, with the introduction of three diversity inputs, through a Ugi reaction followed by intramolecular nucleophilic substitution.

Key words

multicomponent reactions - heterocycles - iso­chromenes - enzymatic acylation - nucleophilic substitutions

    References and Notes

  • 1a Banfi L. Riva R. The Passerini Reaction, In Organic Reactions   Vol. 65:  Overman LE. Wiley; Hoboken: 2005.  p.1-140  
    Google Scholar
  • 1b Passerini M. Gazz. Chim. Ital.  1921,  51:  126 
    Google Scholar
  • 2 Ugi I. Steinbrueckner C. Angew. Chem.  1960,  72:  267 
    CrossrefGoogle Scholar
  • 3a Akritopoulou-Zanze I. Curr. Opin. Chem. Biol.  2008,  12:  324 
    Google Scholar
  • 3b Doemling A. Chem. Rev.  2006,  106:  17 
    Google Scholar
  • 3c Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 
    Google Scholar
  • 4a Akritopoulou-Zanze I. Djuric SW. Heterocycles  2007,  73:  125 
    Google Scholar
  • 4b Hulme C. Nixey T. Bienaymé H. Chenera B. Jones W. Tempest P. Smith AL. Methods Enzymol.  2003,  369:  469 
    Google Scholar
  • 5a Banfi L. Basso A. Cerulli V. Guanti G. Monfardini I. Riva R. Mol. Divers.  2009, in press; DOI: 10.1007/s11030-009-9210-4
    Google Scholar
  • 5b Banfi L. Basso A. Guanti G. Lecinska P. Riva R. Org. Biomol. Chem.  2006,  4:  4236 
    Google Scholar
  • 5c Banfi L. Basso A. Guanti G. Lecinska P. Riva R. Rocca V. Heterocycles  2007,  73:  699 
    Google Scholar
  • 6 Banfi L. Basso A. Guanti G. Kielland N. Repetto C. Riva R. J. Org. Chem.  2007,  72:  2151 
    CrossrefGoogle Scholar
  • 7 Banfi L. Basso A. Guanti G. Lecinska P. Riva R. Mol. Divers.  2008,  12:  187 
    CrossrefGoogle Scholar
  • 8 Banfi L. Basso A. Cerulli V. Guanti G. Riva R. J. Org. Chem.  2008,  73:  1608 
    CrossrefGoogle Scholar
  • 9 Swamy KCK. Kumar NNB. Balaraman E. Kumar KVPP. Chem. Rev.  2009,  109:  2551 
    CrossrefGoogle Scholar
  • 10 Mikami K. Ohmura H. Org. Lett.  2002,  4:  3355 
    CrossrefGoogle Scholar
  • 11 Brown HC. Narasimhan S. Choi YM. J. Org. Chem.  1982,  47:  4702 
    CrossrefGoogle Scholar
  • 12 Schomaker JM. Travis BR. Borhan B. Org. Lett.  2003,  5:  3089 
    CrossrefGoogle Scholar
  • 13 Banfi L. Guanti G. Riva R. Tetrahedron: Asymmetry  1995,  6:  1345 
    CrossrefGoogle Scholar
  • 15 Baciocchi E. Bernini R. Lanzalunga O. Chem. Commun.  1993,  1691 
    Google Scholar
  • 16 Hanessian S. Couture C. Wiss H. Can. J. Chem.  1985,  63:  3613 
    CrossrefGoogle Scholar
  • 22 Cory MG. Richards NGJ. Zerner MC. Modeling the Hydrogen Bond, ACS Symposium Series #569   American Chemical Society; Washington DC: 1994.  p.222-234  
    Google Scholar
14

The aldehyde derived from oxidation of monoacetate 6 could not be used for the preparation of alcohols 10, because acetyl removal after the Ugi reaction brought about cyclization to the phthalide derivatives with elimination of R¹NH2

17

12a and 12b were stable enough to be purified by chromatography and characterized by NMR. However, compound 12a, upon GC-MS analysis, gave a peak corresponding to the cyclized products 13a.

18

Interestingly, treatment of either 11a,b or 12a,b with strong bases (NaH, t-BuOK, LiHMDS) failed to afford any cyclization product. Buffered thermal conditions were needed for this cyclization to occur. In the one-pot procedure (Method A), Et3NH+Cl- was already present in the crude chloride, whereas, in the two-step process (Method B), a triethylammonium salt had to be added.

19

In compounds 13, the protons of all CH2 groups, which should be enantiotopic since there are no stereogenic centres, behave as if they were diastereotopic instead. A partial coalescence of these non-isochronous protons was observed only at 130 ˚C. This phenomenon is likely due to restricted rotation around the C4-N bond, which generates axial chirality.

20

Typical experimental procedure: cyclization of 10h to give 13h. A solution of alcohol 10h (0.50 mmol) in anhydrous CH2Cl2 (3.5 mL) was cooled to -15 ˚C, and treated with Et3N (153 µL, 1.1 mmol) and methanesulfonyl chloride (46 µL, 0.60 mmol). After 1 h, the cooling bath was removed and Et3N (139 µL, 1.0 mmol) was added. After stirring for 1 h at r.t., the solvent was removed under reduced pressure. The residue was taken up in anhydrous DMF (6.5 mL), treated with Et3N (139 µL, 1.0 mmol) and TBAI (92 mg, 0.25 mmol), and stirred at 100 ˚C for 2 h. After cooling, the mixture was treated with sat. aq NH4Cl (25 mL) and H2O (25 mL) and extracted with EtOAc. The organic phases were washed with sat. aq NaCl, evaporated, and purified by chromatography (PE-EtOAc, 85:15) to give pure 13h. R f = 0.69 (PE-acetone, 70:30). ¹H NMR (CDCl3):¹9 δ = 7.45-7.35 (m, 2 H, ArH), 7.33-7.25 (m, 3 H, ArH), 7.21 (dt, J d = 1.2 , J t = 7.5 Hz, 1 H, H-7), 7.02 (d, J = 7.2 Hz, 1 H, H-9), 6.96 (dt, J d = 0.9, J t = 7.3 Hz, 1 H, H-8), 6.65 (d, J = 7.8 Hz, 1 H, H-6), 5.62 (d, J = 13.2 Hz, 1 H, CHHPh), 5.03 and 4.90 (AB system, J = 12.6 Hz, 2 H, H-1), 3.71 (d, J = 13.5 Hz, 1 H, CHHPh), 3.39 (d, J = 8.4 Hz, 1 H, HN), 3.03 (dtt, J t = 4.0, 11.5, J d = 8.0 Hz, 1 H, CHNH), 2.24 (q, J = 7.2 Hz, 2 H, CH 2CH3), 1.75-1.40 (m, 4 H, c-Hexeq CHH), 1.30 (m, 1 H, eq. CHH of c-Hex), 1.13 (tq, J t = 3.1 Hz, J q = 12.9 Hz, 1 H, axial CH2CHHCH2), 1.13-1.02 (m, 1 H, axial CH2CHHCH2), 1.08 (t, J = 7.2 Hz, 3 H, CH 3CH2), 0.94 (tq, J t = 3.0 Hz, J q = 12.3 Hz, 1 H, axial CH2CHHCH2), 0.71 (dq, J d = 3.3 Hz, J q = 11.7 Hz, 1 H, axial CH-CHH-CH2), 0.22 (dq, J d = 3.3 Hz, J q = 11.8 Hz, 1 H, axial CH-CHH-CH2). ¹³C NMR (CDCl3): δ (attribution of signals was made with the aid of HSQC and HMBC experiments) = 177.4 (C=O), 155.1 (C-3), 139.3 (quarternary C of benzyl), 133.0 (C-5), 129.7 (×2), 128.8 (×2), 127.7 (CH of benzyl), 128.8 (C-7), 124.3 (C-10), 123.8 (C-9), 122.5 (C-8), 116.0 (C-6), 93.4 (C-4), 69.2 (C-1), 50.7 (CH2Ph), 50.7 (CHN), 34.3, 33.1, 25.6, 25.1, 24.9 (c-Hex CH2), 25.9 (CH2CH3), 9.6 (CH3). HRMS (EI): m/z [M]+ calcd for C25H30N2O2: 390.2307; found: 390.2235. GC-MS: m/z (%) = 390 (41.1) [M]+, 334 (5.9), 333 (8.2), 299 (71.5), 243 (63.1), 207 (10.4), 206 (8.5), 161 (35.9), 144 (27.6), 143 (4.8), 118 (18.6), 117 (14.0), 116 (19.3), 106 (5.1), 91 (100.0), 89 (8.7), 65 (9.6), 57 (20.7), 55 (19.5), 41 (13.6). IR (CHCl3): 3399, 3012, 2924, 2850, 1625, 1594, 1569, 1447, 1397, 1362, 1347, 1226, 1097, 1073, 917 cm-¹.

21

A pure dry sample of 13a (87.5 mg) was left for 5 days in an open flask on the bench at r.t. After this time, TLC showed that it had completely decomposed, giving a new main spot on the TLC plate. This was isolated by chromatography (PE-acetone, 85:15→70:30). R f = 0.46 (PE-acetone, 75:25). Yield: 45.5 mg (48%). ¹H NMR (CDCl3): δ = 7.54-7.43 (m, 2 H), 7.41-7.30 (m, 2 H), 5.22 (s, 2 H, CH 2O), 4.72 (br t, 1 H, NH), 3.58 (d, J = 7.5 Hz, 2 H, CH 2-iPr), 3.16 (q, J = 6.7 Hz, 2 H, CH 2NH), 2.44 (q, J = 7.4 Hz, 2 H, O=CCH 2CH3), 2.00 [nonuplet, J = 6.8 Hz, 1 H, CH(CH3)2], 1.48 (quint., J = 7.0 Hz, 2 H, NCH2CH 2), 1.38-1.24 (m, 4 H, CH 2CH 2CH3), 1.05 (t, J = 7.4 Hz, 3 H, CH 3CH2), 0.89 [t (covered by the d at 0.88), J = 7.2 Hz, 3 H, CH 3CH2CH2], 0.88 [d, J = 6.8 Hz, 6 H, (CH 3)2CH]. ¹³C NMR (CDCL3): δ (attribution was made also by HSQC and HMBC) = 177.9 (O=CCH2), 173.3 (CCON), 155.9 (OCON), 135.7, 135.2 (C-1, C-2), 131.0, 129.7, 128.1, 127.6 (C-3, C-4, C-5, C-6), 63.9 (CH2O), 52.7 (CH2 of isobutyl), 41.1 (NHCH2), 32.0 (O=CCH2CH3), 29.6 (NCH2 CH2), 28.8 (NCH2CH2 CH2), 28.2 [CH(CH3)2], 22.3 (CCH2CH3), 20.2 [(CH3)2CH], 14.0 (CH3CH2C), 9.7 (CH3CH2CO). HMRS (EI): m/z [M]+ C21H32N2O4: 376.2362; found: 376.2375. GC-MS: m/z (%) = 376 (0.3) [M]+, 347 (5.6), 232 (11.4), 189 (4.0), 146 (19.5), 135 (100.0), 134 (60.1), 133 (9.9), 130 (16.3), 118 (24.4), 105 (6.8), 91 (6.7), 90 (8.3), 86 (12.4), 77 (5.9), 74 (10.5), 57 (25.6), 56 (13.0), 43 (9.9), 41 (9.4). IR (CHCl3): 3445, 2952, 2867, 1709 (s), 1654 (s), 1602, 1461, 1359, 1326, 1183, 1117, 1047 cm-¹.