Skip to main content
SpringerLink
Log in

Recent advances in 1,3-dipolar cycloaddition reactions on solid supports

  • Review
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Solid-phase methods are of a great significance in organic synthesis. Recent developments of these methods are providing new ways to construct libraries of small organic molecules. Five-membered heterocyclic compounds, which can be utilized in a variety of applications, are formed in the 1,3-dipolar cycloaddition reaction between dipolarophiles and dipoles. This review deals with the solid-phase synthesis of heterocycles via [3+2] cycloaddition reaction. Cycloaddition reactions of polymer-bound dipoles and polymer-bound dipolarophiles and intramolecular solid-phase cycloadditions are discussed in separate sections. Reactions of dipolarophiles such as alkenes, alkynes, and imines with dipoles such as azomethine ylides, azomethine imines, nitrile imines, azides, nitrones, and nitrile oxides are described. The recent literature up to December 2003 is covered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Ac:

acetyl

aq:

aqueous

Boc:

t-butoxycarbonyl

Bzl:

benzyl

Cbz:

(benzyloxy)carbonyl

Chx:

cyclohexyl

DBU:

1,8-diazabicyclo[5.4.0]undec-7-ene

DCM:

dichloromethane

DDQ:

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DIC:

1,3-diisopropylcarbodiimide

DIPEA:

N,N-diisopropylethylamine

DIPT:

diisopropyl tartrate

DMAD:

dimethyl acetylenedicarboxylate

DMAP:

4-(dimethylamino)pyridine

DMF:

N,N-dimethylformamide

DMSO:

dimethyl sulfoxide

EDC:

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

ee:

enantiomeric excess

Gly:

glycine

HATU:

O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate

HMDS:

1,1,1,3,3,3-hexamethyldisilazane

Mes:

mesityl

Ms:

methanesulfonyl

NBS:

N-bromosuccinimide

NCS:

N-chlorosuccinimide

PEG:

poly(ethylene glycol)

Phe:

phenylalanine

py:

pyridine

PyBroP:

bromotripyrrolidinophosphonium hexafluorophosphate

rt:

room temperature

TEA:

triethylamine

Tf:

trifluoromethanesulfonyl

TFA:

trifluoroacetic acid

TFFH:

tetramethylfluoroformamidinium hexafluorophosphate

THF:

tetrahydrofuran

THP:

tetrahydropyranyl

TIS:

triisopropylsilane

TMS:

trimethylsilyl

Tos:

p-toluenesulfonyl

TPCD:

[Co(pyridine)4(HCrO4)2].

References

  1. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry, 2 Vols., Wiley, New York, NY, 1984.

    Google Scholar 

  2. Kantorowski, E.J. and Kurth, M.J., Dipolar cycloadditions in solid-phase organic synthesis (SPOS), Mol. Diversity, 2 (1996) 207–216.

    Google Scholar 

  3. Hollinshead, S.P., Stereoselective synthesis of highly functionalised pyrrolidines via 1,3-dipolar cycloaddition reactions on a solid support, Tetrahedron Lett., 37 (1996) 9157–9160.

    Google Scholar 

  4. Dondas, H.A., Grigg, R., MacLachlan, W.S., MacPherson, D.T., Markandu, J., Sridharan, V. and Suganthan, S., Solid phase sequential 1,3-dipolar cycloaddition–Pictet–Spengler reactions, Tetrahedron Lett., 41 (2000) 967–970.

    Google Scholar 

  5. Murphy, M.M., Schullek, J.R., Gordon, E.M. and Gallop, M.A., Combinatorial organic synthesis of highly functionalized pyrrolidines: identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library, J. Am. Chem. Soc., 117 (1995) 7029–7030.

    Google Scholar 

  6. Barrett, A.G.M., Boffey, R.J., Frederiksen, M.U., Newton, C.G. and Roberts, R.S., Pyrrolidine synthesis on polystyrene supports: Development of a ‘one-pot’ dipolar cycloaddition strategy, Tetrahedron Lett., 42 (2001) 5579–5581.

    Google Scholar 

  7. Hoveyda, H.R. and Hall, D.G., Solid-phase synthesis of cleavable N-arylmaleimides: Applications in 1,3-dipolar cycloaddition and in thiol scavenging, Org. Lett., 3 (2001) 3491–3494.

    Google Scholar 

  8. Ganguly, A.K., Seah, N., Popov, V., Wang, C.H., Kuang, R., Saksena, A.K., Pramanik, B.N., Chan, T.M. and McPhail, A.T., Solution- and solid-phase synthesis of enantiomerically pure spiro oxindoles, Tetrahedron Lett., 43 (2002) 8981–8983.

    Google Scholar 

  9. Caix-Haumesser, S., Hanna, I., Lallemand, J.-Y. and Peyronel, J.-F., Solid-phase synthesis of functionalized tropane derivatives via 1,3-dipolar cycloaddition, Tetrahedron Lett., 42 (2001) 3721–3723.

    Google Scholar 

  10. Fuchi, N., Doi, T., Cao, B., Kahn, M. and Takahashi, T., The solid-phase parallel synthesis of β -strand mimetic templates via 1,3-dipolar cycloaddition with resin-bound vinylsulfone, Synlett, (2002) 285-289.

  11. Donohue, A.C., Pallich, S. and McCarthy, T.D., Cycloaddition of nitrile imines to resin-bound enamines: A solid phase synthesis of 1,4-diarylpyrazoles, J. Chem. Soc., Perkin Trans. 1 (2001) 2817–2822.

    Google Scholar 

  12. Garanti, L., Molteni, G. and Casati, P., Nitrilimine cycloadditions to MeOPEG-bounded alkenyl dipolarophiles, J. Chem. Soc., Perkin Trans. 1 (2002) 2504–2508.

    Google Scholar 

  13. Moore, M. and Norris, P., Dipolar cycloaddition reactions on a soluble polymer-supported dipolarophile: Synthesis of sugar-derived triazoles, Tetrahedron Lett., 39 (1998) 7027–7030.

    Google Scholar 

  14. Torn⊘e, C.W., Christensen, C. and Meldal, M., Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides, J. Org. Chem., 67 (2002) 3057–3064.

    Google Scholar 

  15. Kuster, G.J. and Scheeren, H.W., High pressure promoted tandem [4,+,2][3,+,2] cycloadditions on the solid phase, Tetrahedron Lett., 39 (1998) 3613–3616.

    Google Scholar 

  16. Haap, W.J., Kaiser, D., Walk, T.B. and Jung, G., Solid phase synthesis of diverse isoxazolidines via 1,3-dipolar cycloaddition, Tetrahedron, 54 (1998) 3705–3724.

    Google Scholar 

  17. Tan, D.S., Foley, M.A., Shair, M.D. and Schreiber, S.L., Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays, J. Am. Chem. Soc., 120 (1998) 8565–8566.

    Google Scholar 

  18. Tan, D.S., Foley, M.A., Stockwell, B.R., Shair, M.D. and Schreiber, S.L., Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays, J. Am. Chem. Soc., 121 (1999) 9073–9087.

    Google Scholar 

  19. Pisaneschi, F., Della Monica, C., Cordero, F.M. and Brandi, A., Solid-phase access to polyhydroxypyrrolizidines by 1,3-dipolar cycloaddition of (S)-3-alkoxypyrroline N-oxide to maleate and crotonate derivatives, Tetrahedron Lett., 43 (2002) 5711–5714.

    Google Scholar 

  20. Pisaneschi, F., Cordero, F.M. and Brandi, A., Resin linked dipolarophiles to mask nitrones, Synlett, (2003) 1889–1891.

  21. Desimoni, G., Faita, G., Galbiati, A., Pasini, D., Quadrelli, P. and Rancati, F., A soluble polymer-bound Evans chiral auxiliary: Synthesis, characterization and use in cycloaddition reactions, Tetrahedron: Asymmetry, 13 (2002) 333–337.

    Google Scholar 

  22. Park, K.-H., Olmstead, M.M. and Kurth, M.J., Diastereoselective solid-phase synthesis of novel hydantoin- and isoxazoline-containing heterocycles, J. Org. Chem., 63 (1998) 6579–6585.

    Google Scholar 

  23. Park, K.-H. and Kurth, M.J., An uncatalyzed cyclo-elimination process for the release of N3-alkylated hydantoins from solid-phase: Synthesis of novel isoxazoloimidazolidinediones, Tetrahedron Lett., 40 (1999) 5841–5844.

    Google Scholar 

  24. Park, K.-H., Ehrler, J., Spoerri, H. and Kurth, M.J., Preparation of a 990-member chemical compound library of hydantoin- and isoxazoline-containing heterocycles using multipin technology, J. Comb. Chem., 3 (2001) 171–176.

    Google Scholar 

  25. Park, K.-H., Abbate, E., Najdi, S., Olmstead, M.M. and Kurth, M.J., Solution- and solid-phase synthesis of novel hydantoin and isoxazoline-containing heterocycles, J. Chem. Soc., Chem. Commun., (1998) 1679–1680.

  26. Park, K.-H. and Kurth, M.J., Solid-phase synthesis of novel heterocycles containing thiohydantoin and isoxazole rings, J. Org. Chem., 64 (1999), 9297–9300.

    Google Scholar 

  27. Cheng, J.-F. and Mjalli, A.M.M., Solid-phase synthesis of Δ2-isoxazolines, Tetrahedron Lett., 39 (1998) 939–942.

    Google Scholar 

  28. Faita, G., Paio, A., Quadrelli, P., Rancati, F. and Seneci, P., (4S)-p-Hydroxybenzyl-1,3-oxazolidin-2-one as a solid-supported chiral auxiliary in asymmetric 1,3-dipolar cycloadditions, Tetrahedron Lett., 41 (2000) 1265–1269.

    Google Scholar 

  29. Faita, G., Paio, A., Quadrelli, P., Rancati, F. and Seneci, P., Solid supported chiral auxiliaries in asymmetric synthesis. Part 2: Catalysis of 1,3-dipolar cycloadditions by Mg(II) cation, Tetrahedron, 57 (2001) 8313–8322.

    Google Scholar 

  30. Hwang, S.H. and Kurth, M.J., Versatile “traceless” sulfone linker for SPOS: Preparation of isoxazolinopyrrole 2-carboxylates, J. Org. Chem., 67 (2002) 6564–6567.

    Google Scholar 

  31. Lorsbach, B.A., Bagdanoff, J.T., Miller, R.B. and Kurth, M.J., Isoxazolinoisoquinoline heterocycles via solid-phase Reissert and Suzuki reactions, J. Org. Chem., 63 (1998) 2244–2250.

    Google Scholar 

  32. Cheng, W.-C., Wong, M., Olmstead, M.M. and Kurth, M.J., Solid-phase synthesis of novel isoxazolocyclobutanones and isoxazolinocyclobutenones, Org. Lett., 4 (2002) 741–744.

    Google Scholar 

  33. Barrett, A.G.M., Procopiou, P.A. and Voigtmann, U., Solid-phase synthesis of isoxazoles using vinyl ethers as chameleon catches, Org. Lett., 3 (2001) 3165–3168.

    Google Scholar 

  34. Huang, X. and Xu, W.-M., Use of selenium-bound resin for the solid-phase synthesis of substituted isoxazolyl-substituted (E)-olefins, Org. Lett., 5 (2003) 4649–4652.

    Google Scholar 

  35. Wang, H.J., Ling, W. and Lu, L., A novel resin-bound CF3-containing building block: Application to the solid-phase synthesis of CF3-containing acrylates and 4-isoxazolecarboxylates, J. Fluorine Chem., 111 (2001) 241–246.

    Google Scholar 

  36. Makaritis, A., Georgiadis, D., Dive, V. and Yiotakis, A., Diastereoselective solution and multipin-based combinatorial array synthesis of a novel class of potent phosphinic metalloprotease inhibitors, Chem. Eur. J., 9 (2003) 2079–2094.

    Google Scholar 

  37. Shang, Y.-J. and Wang, Y.-G., Soluble polymer-supported synthesis of isoxazoles, Tetrahedron Lett., 43 (2002) 2247–2249.

    Google Scholar 

  38. Komatsu, M., Okada, H., Akaki, T., Oderaotoshi, Y. and Minakata, S., Generation and cycloaddition of polymer-supported azomethine ylide via a 1,2-silatropic shift of α -silylimines: Traceless synthesis of pyrrolidine derivatives, Org. Lett., 4 (2002) 3505–3508.

    Google Scholar 

  39. Okada, H., Akaki, T., Oderaotoshi, Y., Minakata, S. and Komatsu, M., Generation and cycloaddition of polymer-supported azomethine ylide by utilizing the characteristics of silicon: A facile route to pyrrolidines and pyrroles from α -silylimines bound to resin, Tetrahedron, 59 (2003) 197–205.

    Google Scholar 

  40. Washizuka, K.-I., Nagai, K., Minakata, S., Ryu, I. and Komatsu, M., Generation and cycloaddition of polymer-supported azomethine imines: Traceless synthesis of pyrazole derivatives from α-silylnitro- soamide derivatives bound to resin, Tetrahedron Lett., 41 (2000) 691–695.

    Google Scholar 

  41. Kawamura, Y., Akai, Y. and Tsukayama, M., Combinatorial synthesis of exohedrally modified fullerene derivatives, Int. J. Modern Phys. B, 17 (2003) 1910–1915.

    Google Scholar 

  42. Bicknell, A.J., Hird, N.W. and Readshaw, S.A., Efficient robotic synthesis. Multi-component preparation of a tricyclic template by solid phase Tsuge reaction, Tetrahedron Lett., 39 (1998) 5869-5872.

    Google Scholar 

  43. Brooking, P., Crawshaw, M., Hird, N.W., Jones, C., MacLachlan, W.S., Readshaw, S.A. and Wilding, S., The development of a solid phase Tsuge reaction and its application in high throughput robotic synthesis, Synthesis, (1999) 1986–1992.

  44. Goff, D.A., Combinatorial synthesis of indolizines on solid support, Tetrahedron Lett., 40 (1999), 8741–8745.

    Google Scholar 

  45. Strocker, A.M., Keating, T.A., Tempest, P.A. and Armstrong, R.W., Use of a convertible isocyanide for generation of Ugi reaction derivatives on solid support: Synthesis of α -acylaminoesters and pyrroles, Tetrahedron Lett., 37 (1996) 1149–1152.

    Google Scholar 

  46. Mjalli, A.M.M., Sarshar, S. and Baiga, T.J., Solid phase synthesis of pyrroles derived from a four component condensation, Tetrahedron Lett., 37 (1996), 2943–2946.

    Google Scholar 

  47. Bilodeau, M.T. and Cunningham, A.M., Solid-supported synthesis of imidazoles: A strategy for direct resin-attachment to the imidazole core, J. Org. Chem., 63 (1998) 2800–2801.

    Google Scholar 

  48. Gowravaram, M.R. and Gallop, M.A., “Traceless” solid-phase synthesis of furans via 1,3-dipolar cycloaddition reactions of isomünchnones, Tetrahedron Lett., 38 (1997) 6973–6976.

    Google Scholar 

  49. Whitehouse, D.L., Nelson, K.H., Jr, Savinov, S.N. and Austin, D.J., A chemoselective rhodium(II) mediated solid phase 1,3-dipolar cycloaddition and its application to a thermally self-cleaving furan scaffold, Tetrahedron Lett., 38 (1997) 7139–7142.

    Google Scholar 

  50. Whitehouse, D.L., Nelson, K.H., Jr, Savinov, S.N., Löwe, R.S. and Austin, D.J., A metathetical cycloaddition–cycloreversion approach to the formation of furan scaffold libraries, Bioorg. Med. Chem., 6 (1998) 1273–1282.

    Google Scholar 

  51. Savinov, S.N. and Austin, D.J., Diastereofacial solid phase synthesis and self-promoted cleavage of a [2.2.1] bicyclic diversity scaffold, Org. Lett., 4 (2002) 1419–1422.

    Google Scholar 

  52. Löber, S., Rodriguez-Loaiza, P. and Gmeiner, P., Click linker: Efficient and high-yielding synthesis of a new family of SPOS resins by 1,3-dipolar cycloaddition, Org. Lett., 5 (2003) 1753–1755.

    Google Scholar 

  53. Garanti, L. and Molteni, G., MeOPEG-bounded azide cycloadditions to alkynyl dipolarophiles, Tetrahedron Lett., 44 (2003) 1133–1135.

    Google Scholar 

  54. Harju, K., Vahermo, M., Mutikainen, I. and Yli-Kauhaluoma, J., Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition, J. Comb. Chem., 5 (2003) 826–833.

    Google Scholar 

  55. Kuster, G.J. and Scheeren, H.W., The preparation of resin-bound nitroalkenes and some applications in high pressure promoted cycloadditions, Tetrahedron Lett., 41 (2000) 515–519.

    Google Scholar 

  56. Kobayashi, S. and Akiyama, R., Lanthanide triflate-catalyzed 1,3-dipolar cycloaddition reactions of polymer-supported nitrones with alkenes for the preparation of diverse 2-isoxazoline derivatives, Tetrahedron Lett., 39 (1998) 9211–9214.

    Google Scholar 

  57. Shankar, B.B., Yang, D.Y., Girton, S. and Ganguly, A.K., One pot solid phase synthesis of isoxazolines, Tetrahedron Lett., 39 (1998) 2447–2448.

    Google Scholar 

  58. Zou, N. and Jiang, B., Solid phase asymmetric synthesis of isoxazolines, J. Comb. Chem., 2 (2000) 6–7.

    Google Scholar 

  59. Beebe, X., Schore, N.E. and Kurth, M.J., Polymer-supported synthesis of 2,5-disubstituted tetrahydrofurans, J. Am. Chem. Soc., 114 (1992) 10061–10062.

    Google Scholar 

  60. Ockey, D.A., Lane, D.R., Seeley, J.A. and Schore, N.E., Synthesis of cyclic ethers utilizing a cyclization–fragmentation strategy, Tetrahedron, 56 (2000) 711–717.

    Google Scholar 

  61. Lin, X.-F., Cui, S.-L. and Wang, Y.-G., Rapid one-pot solid-phase synthesis of 1,2,4-oxadiazolines, Chem. Lett., 32 (2003) 842–843.

    Google Scholar 

  62. Faita, G., Mella, M., Mortoni, A., Paio, A., Quadrelli, P. and Seneci, P., Solid-supported nitrile oxides as stable and valuable reactive intermediates, Eur. J. Org. Chem., (2002) 1175–1183.

  63. Cereda, E., Ezhaya, A., Quai, M. and Barbaglia, W., Solid-phase synthesis of 3-hydroxymethyl isoxazoles via resin bound nitrile oxides, Tetrahedron Lett., 42 (2001) 4951–4953.

    Google Scholar 

  64. Marx, M.A., Grillot, A.-L., Louer, C.T., Beaver, K.A. and Bartlett, P.A., Synthetic design for combinatorial chemistry. Solution and polymer-supported synthesis of polycyclic lactams by intramolecular cyclization of azomethine ylides, J. Am. Chem. Soc., 119 (1997) 6153–6167.

    Google Scholar 

  65. Gong, Y.-D., Najdi, S., Olmstead, M.M. and Kurth, M.J., Solid-phase synthesis: Intramolecular azomethine ylide cycloaddition (→ proline) and carbanilide cyclization (→ hydantoin) reactions, J. Org. Chem., 63 (1998) 3081–3086.

    Google Scholar 

  66. Peng, G., Sohn, A. and Gallop, M.A., Stereoselective solid-phase synthesis of a triaza tricyclic ring system: A new chemotype for lead discovery, J. Org. Chem., 64 (1999) 8342–8349.

    Google Scholar 

  67. Cironi, P., Manzanares, I., Albericio, F. and Álvarez, M., Solid-phase total synthesis of the pentacyclic system lamellarins U and L, Org. Lett., 5 (2003) 2959–2962.

    Google Scholar 

  68. Chao, E.Y., Minick, D.J., Sternbach, D.D., Shearer, B.G. and Collins, J.L., A novel method for the generation of nitrile oxides on a solid phase: Application to the synthesis of substituted benzopyranoisoxazoles, Org. Lett., 4 (2002) 323–326.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vikki Drug Discovery Technology Center, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, Fl-00014, Helsinki, Finland

    Krsi Harju & Jari Yli-Kauhaluoma

Authors
  1. Krsi Harju
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jari Yli-Kauhaluoma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jari Yli-Kauhaluoma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harju, K., Yli-Kauhaluoma, J. Recent advances in 1,3-dipolar cycloaddition reactions on solid supports. Mol Divers 9, 187–207 (2005). https://doi.org/10.1007/s11030-005-1339-1

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-005-1339-1

Keywords

Search

Navigation