Download PDF
Synlett 2008(15): 2360-2364  
DOI: 10.1055/s-2008-1078210
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Valuable Versatile Reactivity of Thiaisatoic Anhydrides: Expedient Solid­Phase Synthesis of Thieno[1,4]diazepine-2,5-diones

Yann Brouillette, Pascal Verdié, Jean Martinez, Vincent Lisowski*
Institut des Biomolécules Max-Mousseron, UMR 5247, CNRS, Universités Montpellier I et II, UFR de Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France
Fax: +33(4)67548654; e-Mail: vincent.lisowski@univ-montp1.fr;
Further Information

Publication History

Received 3 June 2008
Publication Date:
22 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

An expedient route for the generation of substituted thieno[3,2-e][1,4]diazepine-2,5-dione analogues is described herein. It was demonstrated in solution that thiaisatoic anhydride and its N-alkylated equivalents react in opposite ways with amino acids in basic conditions. This versatile reactivity was used to develop an efficient strategy on solid support. Wang resin-bound thiaisatoic anhydride was coupled with N-alkylated α-amino acids, cyclo-condensed and effectively cleaved from the polymer to provide a preliminary collection of thieno[3,2-e][1,4]diazepine-2,5-diones in 83-99% purity and 71-95% yield.

Key words

1H-thieno[3,2-d][1,3]oxazine-2,4-dione - thiaisatoic anhydride - 3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione - thienodiazepines - solid-phase synthesis

    References and Notes

  • 1 Morel C. Ibarz G. Oiry C. Carnazzi E. Berge G. Gagne D. Galleyrand JC. Martinez J. J. Biol. Chem.  2005,  280:  21384 
    Google Scholar
  • 2 Hynes J. Dyckman AJ. Lin SQ. Wrobleski ST. Wu H. Gillooly KM. Kanner SB. Lonial H. Loo D. McIntyre KW. Pitt S. Shen DR. Shuster DJ. Yang XX. Zhang R. Behnia K. Zhang HJ. Marathe PH. Doweyko AM. Tokarski JS. Sack JS. Pokross M. Kiefer SE. Newitt JA. Barrish JC. Dodd J. Schieven GL. Leftheris K. J. Med. Chem.  2008,  51:  4 
    CrossrefPubMedGoogle Scholar
  • 3 Wagner G. Laufer S. Med. Res. Rev.  2006,  26:  1 
    CrossrefPubMedGoogle Scholar
  • 4 Hynes J. Leftheris K. Curr. Top. Med. Chem.  2005,  5:  967 
    CrossrefPubMedGoogle Scholar
  • 5 Lee MR. Dominguez C. Curr. Med. Chem.  2005,  12:  2979 
    CrossrefPubMedGoogle Scholar
  • 6 Verdie P. Subra G. Feliu L. Sanchez P. Berge G. Garcin G. Martinez J. J. Comb. Chem.  2007,  9:  254 
    CrossrefPubMedGoogle Scholar
  • 7 Clark RL. Carter KC. Mullen AB. Coxon GD. Owusu-Dapaah G. McFarlane E. Thi MDD. Grant MH. Tettey JNA. Mackay SP. Bioorg. Med. Chem. Lett.  2007,  17:  624 
    CrossrefPubMedGoogle Scholar
  • 8 Wang L. Sullivan GM. Hexamer LA. Hasvold LA. Thalji R. Przytulinska M. Tao ZF. Li GQ. Chen ZH. Xiao Z. Gu WZ. Xue J. Bui MH. Merta P. Kovar P. Bouska JJ. Zhang HY. Park C. Stewart KD. Sham HL. Sowin TJ. Rosenberg SH. Lin NH. J. Med. Chem.  2007,  50:  4162 
    CrossrefPubMedGoogle Scholar
  • 9 Henderson EA. Alber DG. Baxter RC. Bithell S K. Budworth J. Carter MC. Chubb A. Cockerill GS. Dowdell VCL. Fraser IJ. Harris RA. Keegan SJ. Kelsey RD. Lumley JA. Stables JN. Weerasekera N. Wilson LJ. Powell KL. J. Med. Chem.  2007,  50:  1685 
    CrossrefPubMedGoogle Scholar
  • 10 Bolli MH. Marfurt J. Grisostomi C. Boss C. Binkert C. Hess P. Treiber A. Thorin E. Morrison K. Buchmann S. Bur D. Ramuz H. Clozel M. Fischli W. Weller T. J. Med. Chem.  2004,  47:  2776 
    CrossrefPubMedGoogle Scholar
  • 11 Churcher I. Williams S. Kerrad S. Harrison T. Castro JL. Shearman MS. Lewis HD. Clarke EE. Wrigley JDJ. Beher D. Tang YS. Liu WS. J. Med. Chem.  2003,  46:  2275 
    Google Scholar
  • 12 Hunt JT. Ding CZ. Batorsky R. Bednarz M. Bhide R. Cho Y. Chong S. Chao S. Gullo-Brown J. Guo P. Kim SH. Lee FYF. Leftheris K. Miller A. Mitt T. Patel M. Penhallow BA. Ricca C. Rose WC. Schmidt R. Slusarchyk WA. Vite G. Manne V. J. Med. Chem.  2000,  43:  3587 
    CrossrefPubMedGoogle Scholar
  • 13 For a review on the chemistry of isatoic anhydride, see: Coppola GM. Synthesis  1980,  505 
    Article in Thieme ConnectGoogle Scholar
  • 14 Beutner GL. Kuethe JT. Yasuda N. J. Org. Chem.  2007,  72:  7058 
    Google Scholar
  • 15 Kamel AA. Abdou WM. Synlett  2007,  1269 
    Article in Thieme ConnectGoogle Scholar
  • 16 Labrie P. Maddaford SP. Lacroix J. Catalano C. Lee DKH. Rakhit S. Gaudreault RC. Bioorg. Med. Chem.  2007,  15:  3854 
    CrossrefPubMedGoogle Scholar
  • 17 Snider BB. Wu XX. Org. Lett.  2007,  9:  4913 
    CrossrefPubMedGoogle Scholar
  • 18 Brouillette Y. Lisowski V. Guillon J. Massip S. Martinez J. Tetrahedron  2007,  63:  7538 
    CrossrefGoogle Scholar
  • 19 Brouillette Y. Lisowski V. Martinez J. J. Org. Chem.  2007,  72:  2662 
    CrossrefPubMedGoogle Scholar
  • 20 Bunnett JF. Naff MB. J. Am. Chem. Soc.  1966,  88:  4001 ; and cited references therein
    CrossrefGoogle Scholar
  • For a review on the recent advances in the solid-phase combinatorial synthetic strategies of the benzodiazepine-based privileged structures, see:
  • 21a Kamal A. Reddy KL. Devaiah V. Shankaraiah N. Reddy DR. Mini-Rev. Med. Chem.  2006,  6:  53 
    Google Scholar
  • 21b Kamal A. Shankaraiah N. Prabhakar S. Ratna ReddyC. Markandeya N. Laxma ReddyK. Devaiah V. Bioorg. Med. Chem. Lett.  2008,  18:  2434 
    Google Scholar
  • 22 Boojamra CG. Burow KM. Thompson LA. Ellman JA. J. Org. Chem.  1997,  62:  1240 
    CrossrefGoogle Scholar
  • 23 Fabis F. Jolivet-Fouchet S. Rault S. Tetrahedron  1999,  55:  6167 
    CrossrefGoogle Scholar
  • 24 Breznik M. Grdadolnik SG. Giester G. Leban I. Kikelj D. J. Org. Chem.  2001,  66:  7044 
    Google Scholar
  • 25 Wang SS. J. Am. Chem. Soc.  1973,  95:  1328 
    CrossrefPubMedGoogle Scholar
  • 26 Lu G. Mojsov S. Tam JP. Merrifield RB. J. Org. Chem.  1981,  46:  3433 
    CrossrefGoogle Scholar
  • 27 Zoller T. Ducep JB. Hibert M. Tetrahedron Lett.  2000,  41:  9985 
    Google Scholar
  • 28 Raju B. Kogan TP. Tetrahedron Lett.  1997,  38:  4965 
    CrossrefGoogle Scholar
  • 29 Ngu K. Patel DV. Tetrahedron Lett.  1997,  38:  973 
    CrossrefGoogle Scholar
  • 30 Coppola GM. Tetrahedron Lett.  1998,  39:  8233 
    Google Scholar
  • 31 Kamal A. Reddy KL. Devaiah V. Shankaraiah N. Synlett  2004,  1841 
    Article in Thieme ConnectGoogle Scholar
  • 32 Macleod C. Martinez-Teipel BI. Barker WM. Dolle RE. J. Comb. Chem.  2006,  8:  132 
    CrossrefPubMedGoogle Scholar
  • 33 Harju K. Vahermo M. Mutikainen I. Yli-Kauhaluoma J. J. Comb. Chem.  2003,  5:  826 
    CrossrefPubMedGoogle Scholar
  • 34 Phoon CW. Sim MM. Synlett  2001,  697 
    Google Scholar
35

Typical Experimental Procedure for the Ring Opening of Thiaisatoic Anhydrides 5 and 6
A stirring suspension of N-p-methoxybenzylthieno[3,2-d][1,3]oxazine-2,4-dione (6, 7.00 g, 24.22 mmol) and the corresponding α-amino acid (26.64 mmol) in H2O (100 mL) was treated with Et3N (7.43 mL, 53.29 mmol) at r.t. for 30 min. Drops of DMF can be added to favor complete solubility. The resulting solution was partitioned with EtOAc. The aqueous phase was extracted with EtOAc (3 × 40 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to afford the corresponding product 8.
Acid 8e: white solid, mp 68-70 ˚C; [α]D ²0 -18.7 (c 0.3, DMSO). ¹H NMR (300 MHz, DMSO-d 6): δ = 7.57 (m, 2 H), 7.46 (d, 1 H, J = 5.4 Hz), 7.26 (m, 5 H), 7.22 (d, 2 H, J = 7.3 Hz), 6.87 (d, 2 H, J = 7.1 Hz), 6.74 (d, 1 H, J = 5.4 Hz), 4.52 (q, 1 H, J = 8.0), 4.31 (d, 2 H, J = 5.5), 3.71 (s, 3 H), 3.10 (d, 2 H, J = 8.0 HZ). ¹³C NMR (75 MHz, DMSO-d 6): δ = 173.4, 164.6, 158.3, 154.5, 138.3, 131.8, 129.1, 129.0, 128.4, 128.1, 126.3, 117.6, 113.9, 100.6, 55.0, 53.6, 47.5, 36.1. HRMS: m/z calcd for [M + H+] C22H23N2O4S: 411.1379; found: 411.1360.

36

Typical Experimental Procedure for the Synthesis of Thieno[3,2- e ][1,4]diazepinediones 9 and 10
A solution of acid 8 in AcOH was magnetically stirred at reflux for 1-6 h. The resulting solution was concentrated under reduce pressure and triturated with Et2O to afford the corresponding thienodiazepine 10. This procedure can be directly applied to the crude mixture of acids 7 and 8, after evaporation of volatile material, to attain a one-flask protocol directly to thienodiazepines 9 and 10. The workup remains the same.
(S)-1-(4-Methoxybenzyl)-3-benzyl-3,4-dihydro-1H-thieno[3,2-e][1,4]diazepine-2,5-dione (10e): orange solid, mp 66-68 ˚C; [α]D ²0 +27.5 (c 0.1, DMSO). ¹H NMR (300 MHz, DMSO-d 6): δ = 8.50 (d, 1 H, J = 3.5 Hz), 7.81 (d, 1 H, J = 5.3 Hz), 7.37-7.20 (m, 6 H), 7.03 (d, 2 H, J = 8.5 Hz), 6.81 (d, 2 H, J = 8.6 Hz), 5.23 (d, 1 H, J = 15.5 Hz), 4.89 (d, 1 H, J = 15.5 Hz), 4.17 (m, 1 H), 3.68 (s, 3 H), 3.24 (dd, 1 H, J = 13.8, 5.3 Hz), 2.98 (dd, 1 H, J = 13.5, 9.0 Hz). ¹³C NMR (75 MHz, DMSO-d 6): δ = 168.6, 162.8, 158.4, 140.4, 137.8, 130.8, 129.5, 128.9, 128.4, 128.2, 126.5, 124.9, 122.7, 113.9, 55.0, 55.0, 48.6, 34.3. HRMS: m/z calcd for C22H21N2O3S [M + H+]: 393.1273; found: 393.1298; R f = 0.4 (CHCl3-EtOAc, 4:1).

37

General SPS Procedure
Wang bromide resin (5.0 g, 1.6 mmol/g) was swollen in 50 mL of DMF, treated with anhydride 1 (2.03 g, 12.0 mmol) and K2CO3 (2.21 g, 16.0 mmol) for 1 h at r.t. and sequentially washed with H2O, DMF, and CH2Cl2 to afford the beige resin-bound anhydride 11. Thienodiazepine resin 13 was synthesized by treating a suspension of resin 11 (0.400 g, 0.56 mmol) in DMF-H2O (10 mL, 4:1) with the respective amino acid (500 mol%) and Et3N (1000 mol%) for 5 h at 50 ˚C, and then washed with DMF, H2O, and CH2Cl2. Thienodiazepines 14 were obtained by treating diazepine resin 13 (0.400 g, 0.52 mmol) with TFA-CH2Cl2 (8 mL, 1:1) for 24 h.
(S)-3,4-Dihydro-3,4-dimethylthieno[3,2-e][1,4]diazepine-2,5-dione (14b): beige solid, mp 191-194 ˚C; [α]D ²0 +51.6 (c 0.1, DMSO). ¹H NMR (300 MHz, DMSO-d 6): δ = 10.91 (s, 1 H), 7.78 (d, 1 H, J = 5.1 Hz), 6.80 (d, 1 H, J = 5.1 Hz), 4.20 (q, 1 H, J = 6.9 Hz), 2.93 (s, 3 H), 1.34 (d, 3 H, J = 7.0). ¹³C NMR (75 MHz, DMSO-d 6): δ = 169.2, 162.5, 138.1, 131.4, 128.5, 121.3, 54.7, 30.8, 12.6. HRMS: m/z calcd for C8H11N2O2S [M + H+]: 211.0541; found: 211.0575.