Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The partial reduction of electron-deficient pyrroles: procedures describing both Birch (Li/NH3) and ammonia-free (Li/DBB) conditions


The partial reduction of electron-deficient pyrroles using either Birch (Li/NH3) or ammonia-free (Li/di-tert-butyl biphenyl) conditions allows formation of pyrroline compounds in good yield and, when combined with a reductive alkylation or similar approach, leads to highly functionalized, synthetically useful compounds. This methodology has been proven in the syntheses of several complex natural products, all of which show interesting biological activity. This protocol describes in detail the following stages of the partial reduction procedure: formation of the reducing solution, partial reduction of the pyrrole compound and finally quench of the resulting anion/dianion using either protonating agents or an aldehyde. The ammonia-free conditions described herein are particularly useful for reactions requiring the use of reactive electrophiles, such as acid chlorides or enolizable aldehydes, which are incompatible with the standard Birch reduction conditions. The reaction procedure for the ammonia Birch reduction (procedure A) takes about 9.5 h to complete. Those described for the ammonia-free reductions, procedure B and procedure C, can be expected to take approximately 33 and 8 h, respectively.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7


  1. Donohoe, T.J. & House, D. Ammonia free reduction of aromatic compounds using lithium di-tert-butylbiphenyl (LiDBB). J. Org. Chem. 67, 5015–5018 (2002).

    CAS  Article  Google Scholar 

  2. Donohoe, T.J., Guyo, P.M., Harji, R.R. & Cousins, R.P.C. The Birch reduction of 3-substituted pyrroles. Tetrahedron Lett. 39, 3075–3078 (1998).

    CAS  Article  Google Scholar 

  3. Donohoe, T.J., Guyo, P.M. & Helliwell, M. The stereoselective Birch reduction of pyrroles. Tetrahedron Lett. 40, 435–438 (1999).

    CAS  Article  Google Scholar 

  4. Donohoe, T.J., Helliwell, M., Stevenson, C.A. & Ladduwahetty, T. Stereoselectivity in the Birch reduction of 2-furoic acid derivatives. Tetrahedron Lett. 39, 3071–3074 (1998).

    CAS  Article  Google Scholar 

  5. Donohoe, T.J., Guillermin, J.-B., Frampton, C. & Walters, D.S. The synthesis of (+)-nemorensic acid. Chem. Commun. 465–466 (2000).

  6. Donohoe, T.J., Mace, L.H., Helliwell, M. & Ichihara, O. Transformations of 3,4-disubstituted pyridines under dissolving metal conditions-partial reduction followed by radical cyclisation. Synlett 331–333 (2002).

  7. Donohoe, T.J., McRiner, A.J. & Sheldrake, P. Partial reduction of electron deficient pyridines. Org. Lett. 2, 3861–3863 (2000).

    CAS  Article  Google Scholar 

  8. Donohoe, T.J., Johnson, D.J., Mace, L.H., Bamford, M.J. & Ichihara, O. Partial reduction of pyridinium salts as a versatile route to dihydropyridones. Org. Lett. 7, 435–437 (2005).

    CAS  Article  Google Scholar 

  9. Donohoe, T.J. & Guyo, P.M. Birch reduction of electron-deficient pyrroles. J. Org. Chem. 61, 7664–7665 (1996).

    CAS  Article  Google Scholar 

  10. Donohoe, T.J., House, D. & Ace, K.W. Scope of the reductive aldol reaction: application to aromatic carbocycles and heterocycles. Org. Biomol. Chem. 1, 3749–3757 (2003).

    CAS  Article  Google Scholar 

  11. Donohoe, T.J. & House, D. Diastereoselective reductive aldol reactions of Boc-protected electron deficient pyrroles. Tetrahedron Lett. 44, 1095–1098 (2003).

    CAS  Article  Google Scholar 

  12. Carbery, D.R. & Donohoe, T.J. Enantiopure oxazolidinones as chiral acids in the asymmetric protonation of N-Boc pyrrole derived enolates. Chem. Commun. 722–723 (2004).

  13. Donohoe, T.J. et al. Enantioselective partial reduction of 2,5-disubstituted pyrroles via a chiral protonation approach. Org. Lett. 6, 3055–3058 (2004).

    CAS  Article  Google Scholar 

  14. Donohoe, T.J., Headley, C.E., Cousins, R.P.C. & Cowley, A. Flexibility in the partial reduction of 2,5-disubstituted pyrroles: application to the synthesis of DMDP. Org. Lett. 5, 999–1002 (2003).

    CAS  Article  Google Scholar 

  15. Donohoe, T.J. & Thomas, R.E. Formation of N-Boc pyrrole 2,5-methyl diester, a key intermediate in the Donohoe synthesis of 1-epiaustraline and hyacinthacine A1 . Nat. Protoc. DOI: 10.1038/nprot.2007.232 (2007).

  16. Donohoe, T.J. et al. Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20S proteasome inhibitor, clasto-lactacystin β-lactone. Chem. Eur. J. 11, 4227–4238 (2005).

    CAS  Article  Google Scholar 

  17. Donohoe, T.J. & Thomas, R.E. Formation of N-Boc pyrrole 2-ethyl ester, a key intermediate in the Donohoe synthesis of omuralide. Nat. Protoc. DOI: 10.1038/nprot.2007.231 (2007).

  18. Donohoe, T.J. & Sintim, H.O. A concise total synthesis of (±)-1-epiaustraline. Org. Lett. 6, 2003–2006 (2004).

    CAS  Article  Google Scholar 

  19. Donohoe, T.J., Sintim, H.O. & Hollinshead, J. A noncarbohydrate based approach to polyhydroxylated pyrrolidizines: total syntheses of the natural products hyacinthacine A1 and 1-epiaustraline. J. Org. Chem. 70, 7297–7304 (2005).

    CAS  Article  Google Scholar 

  20. Donohoe, T.J., Sintim, H.O., Sisangia, L. & Harling, J.D. An efficient synthesis of lactacystin β-lactone. Angew. Chem. Int. Ed. 43, 2293–2296 (2004).

    CAS  Article  Google Scholar 

  21. Curtis, M.D. & Allred, A.L. Electron spin resonance spectra of some group IV-B substituted biphenyl anion radicals. Dative π-bonding. J. Am. Chem. Soc. 87, 2554–2563 (1965).

    CAS  Article  Google Scholar 

  22. Rieke, R.D., Bales, S.E., Hudnall, P.M., Burns, T.P., Poindexter, G.S. Highly reactive magnesium for the preparation of Grignard reagents: 1-norbornanecarboxylic acid. Org. Synth. Coll. Vol. 6, 845–851 (1988); 59, 85–91 (1979).

    Google Scholar 

  23. Pangborn, A.B., Giardello, M.A., Grubbs, R.H., Rosen, R.K. & Timmers, F.J. Safe and convenient procedure for solvent purification. Organometallics 15, 1518–1520 (1996).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Timothy J Donohoe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Donohoe, T., Thomas, R. The partial reduction of electron-deficient pyrroles: procedures describing both Birch (Li/NH3) and ammonia-free (Li/DBB) conditions. Nat Protoc 2, 1888–1895 (2007).

Download citation

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing