Intramolecular Carbolithiation of Alkynes: Observation, Mechanism, Applications

Abstract

The intramolecular carbolithiation of alkynes is a useful cyclization reaction that gives stereoselective access to functionalized alkenes. This reaction is supposed to proceed through a syn-addition mechanism. We show in this account that the interaction between the lithium cation and the substituent on the propargylic position (or directly on the triple bond) can derail this process and afford selectively the anti-addition product. The set of results presented in this account, both experimental and theoretical, suggests that the stereochemical outcome of the addition can be predicted with success.

Keywords

Alkynes - Carbolithiation - Cyclization - Heterocycles - Lithium coordination - Stereoselectivity

Publication History

Received: 16 September 2025

Accepted after revision: 27 October 2025

Accepted Manuscript online:
27 October 2025

Article published online:
27 November 2025

• References

• 1a Ziegler K, Bähr K. Chem Ber 1928; 253-263
• 1b Sinn H, Kaminsky W. Adv Organomet Chem 1980; 99-149
• 1c Kashiwa N. J Polym Sci Part A Polym Chem 2004; 42: 1-8
• 2a Normant JF, Alexakis A. Synthesis 1981; 841
• 2b Negishi EI. Pure Appl Chem 1981; 53: 2333
• 2c Knochel P. In: Comprehensive Organic Synthesis. Trost B. ed Vol 4. New York: Pergamon press; 1991: 865
• 2d Fallis AG, Forgione P. Tetrahedron 2001; 57: 5899
• 2e Marek I, Chinkov N, Banon-Tenne D. In: Metal-Catalyzed Cross-Coupling Reactions. de Meijere A, Diedeich F. eds. Vol 1. 2nd ed Weinheim: Wiley-WCH; 2004: 395
• 2f Dénès F, Pérez-Luna A, Chemla F. Chem Rev 2010; 110: 2366
• 3a Marek I, Basheer A. In: Science of Synthesis, Stereoselective Synthesis 1. de Vries JG, Evans PA, Molander GA. eds. Vol 1. 1st ed Stuttgart: Georg Thieme Verlag; 2011: 325
• 3b Ding A, Guo H. In: Comprehensive Organic Synthesis II. Knochel P. ed. Vol 4. 2nd ed Amsterdam: Elsevier; 2014: 891
• 4a Le Strat F, Maddaluno J. Org Lett 2002; 4: 2791
• 4b Ahmad M, Gaumont A-G, Durandetti M, Maddaluno J. Angew Chem Int Ed 2017; 56: 2464-2468
• 5a Durandetti M, Hardou L, Clément M, Maddaluno J. Chem Commun 2009; 4753-4755
• 5b Durandetti M, Hardou L, Lhermet R, Rouen M, Maddaluno J. Chem Eur J 2011; 17: 12773-12783
• 6 Le Strat F, Maddaluno J. Org Lett 2002; 4: 2791
• 7 Le Strat F, Maddaluno J. Tetrahedron Lett 2000; 41: 5367-5371
• 8 Le Strat F, Vallette H, Toupet L, Maddaluno JE. J Org Chem 2005; 5296

For recent reviews on dearomatization of heterocycles, see:
• 9a Wertjes WC, Southgate EH, Sarlah D. Chem Soc Rev 2018; 47: 7996-8017
• 9b Nair SR, Baire B, Asian J. Org Chem 2021; 10: 932-948
• 9c Zheng C, You S-L. ACS Cent Sci 2021; 7: 432-444
• 9d Rkein B, Manneveau M, Noël-Duchesneau L. et al. Chem Commun 2021; 57: 10071-10074
• 9e Abou-Hamdan H, Kouklovsky C, Vincent G. Synlett 2020; 1775-1788
• 10a Fressigné C, Girard A-L, Durandetti M, Maddaluno J. Angew Chem Int Ed 2008; 47: 891-893
• 10b Fressigné C, Girard A-L, Durandetti M, Maddaluno J. Chem Eur J 2008; 14: 5159-5167
• 10c Fressigné C, Girard A-L, Durandetti M, Maddaluno J. Eur J Org Chem 2009; 721-729
• 11 Hédouin M, Barthelemy A-L, Vanthuyne N. et al. Angew Chem Int Ed 2023; e202214106
• 12a Girard A-L, Lhermet R, Fressigné C, Durandetti M, Maddaluno J. Eur J Org Chem 2012; 2895-2905
• 12b Fressigné C, Lhermet R, Girard A-L, Durandetti M, Maddaluno J. J Org Chem 2013; 78: 9659-9669
• 13 Clayden J. In: Organolithiums: Selectivity for Synthesis. Baldwin JE, Williams RM. eds Oxford: Pergamon, Elsevier Science Ltd.; 2002: 115-117
• 14 Lemiegre L, Stevens RL, Combret J-C, Maddaluno J. Org Biomol Chem 2005; 3: 1308-1318
• 15 Bailey WF, Ovaska TV, Leipert TK. Tetrahedron Lett 1989; 30: 3901-3904

For pionering work see:
• 16 Bailey WF, Ovaska TV. J Am Chem Soc 1993; 115: 3080-3090
• 17 Funk RL, Bolton GL, Brummond KM, Ellestad KE, Stallman JB. J Am Chem Soc 1993; 115: 7023
• 18a Ashweek NJ, Coldham I, Snowden DJ, Vennall GP. Chem Eur J 2002; 8: 195
• 18b Gralla G, Wibbeling B, Hoppe D. Org Lett 2002; 4: 2193
• 18c Hanna R, Daoust B. Tetrahedron 2011; 67: 92
• 19 Lhermet R, Ahmad M, Hauduc C, Fressigné C, Durandetti M, Maddaluno J. Chem Eur J 2015; 21: 8105-8111
• 20a Normant J-F. Bull Soc Chim Fr 1963; 1876
• 20b Moyano A, Charbonnier F, Greene AE. J Org Chem 1987; 52: 2919
• 20c Kann N, Bernardes V, Greene AE. Org Synth 1997; 14: 13
• 21 Granander J, Eriksson J, Hilmersson G. Tetrahedron Asymmetry 2006; 17: 2021-2027
• 22 Kurtz KCM, Hsung RP, Zhang Y. Org Lett 2006; 8: 231-234
• 23a Close WJ. J Org Chem 1950; 15: 1131-1134
• 23b Roder H, Helmchen G, Peters EM, Peters K, von Schnering H-G. Angew Chem 1984; 96: 895-896
• 23c Roder H, Helmchen G, Peters EM, Peters K, von Schnering H-G. Angew Chem Int Ed Engl 1984; 23: 898
• 23d Durandetti M, Périchon J, Nédélec JY. J Org Chem 1997; 62: 7914-7915
• 24a Durand-Reville T, Gobbi LB, Gray BL, Ley SV, Scott JS. Org Lett 2002; 4: 3847
• 24b Corey EJ, Fuchs PL. Tetrahedron Lett 1972; 13: 3769
• 25a Cahiez G, Gager O, Buendia J. Angew Chem 2010; 122: 1300-1303
• 25b Cahiez G, Gager O, Buendia J. Angew Chem Int Ed 2010; 49: 1278-1281
• 26 Lhermet R, Ahmad M, Fressigné C, Silvi B, Durandetti M, Maddaluno J. Chem Eur J 2014; 20: 10249-10254
• 27a Baumann M, Köbrich G. Tetrahedron Lett 1974; 15: 1217-1220
• 27b Braun M. Angew Chem Int Ed 1998; 37: 430-451
• 27c Boche G, Lohrenz JCW. Chem Rev 2001; 101: 697-756
• 27d Braun M. In: Chemistry of Organolithium Compounds. Rappoport Z, Marek I. eds Chichester: J. Wiley & Sons; 2006: 829-900 Chap. 13
• 27e Capriati V, Florio S. Chem Eur J 2010; 16: 4152-4162