[4529-04-8]  · C3H3Li  · Propynyllithium  · (MW 46.00)

(powerful nucleophilic source of the propynyl unit for many electrophiles)

Solubility: sol liquid ammonia; partially sol THF, ether.

Form Supplied in: white suspension in THF; prepared in situ and used directly.

Preparative Methods: prepared in situ under nitrogen by reaction of propyne (condensed into cold THF) with n-Butyllithium in THF at -78 °C2 or Lithium Amide in ether/liquid ammonia below -50 °C,3 or by reaction of 1,2-dibromopropane with 3 equiv of Lithium Diisopropylamide (double elimination of hydrogen bromide and deprotonation) at -60 °C to 0 °C in THF.4

Handling, Storage, and Precautions: must be prepared and transferred under inert gas (Ar or N2) to exclude oxygen and moisture.

Additions to Carbonyl Compounds.

Propynyllithium adds readily to aldehydes and ketones to give the corresponding secondary and tertiary alcohols. The reaction with isobutyraldehyde at -78 °C gives a precursor to the (+)-Prelog-Djerassi lactone after oxidation and enantioselective ketone reduction (eq 1).2 Additions proceed under nonchelation-controlled conditions and are less stereoselective than the corresponding additions of Propynylmagnesium Bromide.5 The linear nature of the reagent allows addition to hindered ketones to give the propargylic alcohols which can be transformed into allenyl sulfoxides with Benzenesulfenyl Chloride (eq 2).6 Propynyllithium prepared from 1,2-dibromopropane also reacts smoothly with aldehydes and ketones in high yield (eq 3).4

Direct methylation of the lithium alkoxide, formed from addition of propynyllithium to easily enolizable ketones such as cyclopentanone and cyclohexanone, with Iodomethane is achieved by addition of a polar cosolvent such as Dimethyl Sulfoxide (eq 4).7 Optimum results are observed with 50 mol % of anhydrous Lithium Bromide as an additive and a ratio of hexane/THF/DMSO of 2:2:3. Alkylation of the adduct formed from propynyllithium and dimethyl squarate with a propargyl iodide gives the cyclobutenone (1), which undergoes thermolysis in refluxing xylene to give the methylenebenzofuran (2) (eq 5).8

Additions to Carboxylic Acid Derivatives.

Propynyllithium adds to valerolactone9 at low temperature and to N,N-dialkyl carboxamides10 to give the corresponding acetylenic ketones after acidic workup. Boron Trifluoride Etherate has been used to promote the coupling to elaborate the side chain of pseudomonic acid C (eq 6).11 Alternatively, reaction with anhydrous Zinc Chloride in THF produces propynylzinc chloride, which couples smoothly with acid chlorides.10

Additions to Epoxides.

Propynyllithium, generated in ether/liquid ammonia by the addition of propyne and ether to a suspension of lithium amide at -50 °C, reacts with Ethylene Oxide to give the b-hydroxyalkylated product (eq 7). The reaction is sluggish in THF or ether and fails with the sodio derivative.3 Boron trifluoride has been used to promote epoxide opening in an approach to rifamycin (eq 8).12

Reactions with Other Electrophiles.

Lithium 1-propynyltrialkylborates, formed by addition of propynyllithium to trialkylboranes, react with Trimethylsilylmethyl Trifluoromethanesulfonate followed by protonolysis to give allylsilanes (eq 9).13 Propynyllithium displaces the nitro group of 3-nitro-4,5-dihydroisoxazole to give a precursor for deoxy-3-aminohexoses,14 and reacts with the hindered aromatic chlorophosphine to give the 3H-phosphaallene after rearrangement (eq 10), while the less basic propynylmagnesium bromide gives the tautomeric alkynyl-1H-phosphine.15 N,N-Bis(trimethylsilyl) ynamines, synthetic equivalents for primary ynamines, have been prepared by addition of propynyllithium to the crystalline hindered hydroxylamine mesitylenesulfonate (eq 11).16

Related Reagents.

The lithium derivatives of various protected forms of propargyl alcohol display very similar reactivity. 3-Tetrahydropyranyloxy-1-propyne, after lithiation in THF with n-BuLi, selectively displaces the bromide of 1-chloro-3-bromopropane after 20 h at 70 °C17 or couples with one end of 1,3-dibromopropane in the presence of Hexamethylphosphoric Triamide.18 The sluggishness of these alkylations has been overcome by the use of triflate as the leaving group and a mixed solvent system of THF-N,N-Dimethylpropyleneurea (6:1). Under these conditions, the TBS ether of propargyl alcohol, after lithiation, displaces the primary triflate, which is a particularly difficult substrate due to the b-oxygen functionality, in 10 min at -20 °C (eq 12).19 The a-ethoxyethyl ether of propargyl alcohol, after lithiation in THF with n-BuLi, has been used in a double addition to a dione in an approach to [5]peristylane (eq 13).20

Related Reagents.

3-Chloro-1-propynyllithium; 1-Lithio-3-trimethylsilyl-1-propyne; Lithium Acetylide; Lithium (Trimethylsilyl)acetylide; Propynylmagnesium Bromide.

1. Brandsma, L. Preparative Acetylene Chemistry, 2nd ed.; Elsevier: Amsterdam, 1988.
2. Tsai, D. J.-S.; Midland, M. M. JACS 1985, 107, 3915.
3. Verkruijsse, H. D.; Brandsma, L. SC 1991, 21, 235.
4. Gribble, G. W.; Joyner, H. H.; Switzer, F. L. SC 1992, 22, 2997.
5. Jacobi, P. A.; Selnick, H. G. JOC 1990, 55, 202.
6. Neef, G.; Eder, U.; Seeger, A. TL 1980, 21, 903.
7. Van Rijn, P. E.; Mommers, S.; Visser, R. G.; Verkruijsse, H. D.; Brandsma, L. S 1981, 459.
8. Xu, S. L.; Taing, M.; Moore, H. W. JOC 1991, 56, 6104.
9. Schreiber, S. L.; Kelly, S. E. TL 1984, 25, 1757.
10. Verkruijsse, H. D.; Heus-Kloos, Y. A.; Brandsma, L. JOM 1988, 338, 289.
11. Barrish, J. C.; Lee, H. L.; Baggiolini, E. G.; Uskokovic, M. R. JOC 1987, 52, 1372.
12. Katsuki, T.; Hanamoto, T.; Yamaguchi, M. CL 1989, 117.
13. Wang, K. K.; Yang, K. E. TL 1987, 28, 1003.
14. Wade, P. A.; Rao, J. A.; Bereznak, J. F.; Yuan, C. K. TL 1989, 30, 5969.
15. Märkl, G.; Reitinger, S. TL 1988, 29, 463.
16. Weigmann, R. H.; Würthwein, E. U. TL 1989, 30, 6147.
17. Corey, E. J.; Sachdev, H. S. JACS 1973, 95, 8483.
18. Danishefsky, S.; McKee, R.; Singh, R. K. JACS 1977, 99, 4783.
19. Kotsuki, H.; Kadota, I.; Ochi, M. TL 1990, 31, 4609.
20. Eaton, P. E.; Srikrishna, A.; Uggeri, F. JOC 1984, 49, 1728.

Nicholas Greeves

University of Liverpool, UK

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