[108-48-5]  · C7H9N  · 2,6-Lutidine  · (MW 107.17)

(basic reagent/catalyst for silylation of alcohols,2-10 for Rosenmund reduction,14 and for preparation of boron enolates15)

Physical Data: colorless oily liquid with an odor of pyridine and peppermint; bp 144.0 °C/760 mmHg, 79 °C/87 mmHg; mp -5.9 °C; d (20 °C) 0.9252 g cm-3; n20D 1.49797. The major synthetic applications reported for 2,6-lutidine exploit its weakly nucleophilic nature (a result of steric crowding at the ring nitrogen) but moderately basic character (pKa of its conjugate acid is 6.7).

Solubility: sol common organic solvents (e.g. ether, THF, DMF, alcohol); shows considerable water solubility (ca. 27% (w/w) at 45 °C).

Form Supplied in: a widely available article of commerce. Redistilled (99+ % purity) is available commercially. Drying: commonly dried by treatment with KOH or sodium followed by distillation, or by refluxing with, followed by distillation from, BaO1 or CaH2.2

Purification: both 3- and 4-picolines are common contaminants which can be removed by distillation from AlCl3 (14 g/100 mL 2,6-lutidine, which also removes traces of water), or by addition of BF3 (4 mL/100 mL of 2,6-lutidine) to anhydrous, fractionally distilled 2,6-lutidine, followed by redistillation.1

Handling, Storage, and Precautions: toxic flammable liquid; should be handled with caution in a fume hood.

Alcohol Protection Reactions.

The protection of alcohols as hindered silyl ethers proceeds in >90% yield using the appropriate trialkylsilyl triflate in the presence of anhydrous 2,6-lutidine as an acid scavenger. Triisopropylsilyl Trifluoromethanesulfonate/2,6-lutidine in CH2Cl2 (-78 °C to 0 °C) allows for the protection of primary and secondary (but not tertiary) alcohols (eq 1).2,3 Tertiary alcohols can be protected as the somewhat less crowded i-PrEt2Si ether (i-PrEt2SiOTf/2,6-lutidine, CH2Cl2, rt).4 The silylation of tertiary and unreactive secondary alcohols can also be achieved using t-Butyldimethylsilyl Trifluoromethanesulfonate/2,6-lutidine in CH2Cl2 (0-25 °C);2,5 silylation at -78 °C allows for the selective protection of a secondary alcohol in the presence of a secondary allylic alcohol (eq 2).6 The silylation of secondary allylic alcohols as the bulky tribenzylsilyl ether or tri-p-xylylsilyl ether can be accomplished using the appropriate tris(arylmethyl)chlorosilane/2,6-lutidine in DMF at -20 °C.7 The bis-protection of 1,2-, 1,3-, and 1,4-diols as the corresponding dialkylsilylene derivatives can be achieved in high yield using Diisopropylsilyl Bis(trifluoromethanesulfonate) or Di-t-butylsilyl Bis(trifluoromethanesulfonate) at rt in CDCl3 in the presence of 2,6-lutidine (eq 3);8 interestingly, 2,6-lutidine was found to retard the 3,5-protection of nucleosides in DMF solution.9 Protection of a 1,3-diol as its methylene acetal can be achieved using Trimethylsilyl Trifluoromethanesulfonate/2,6-lutidine in MeOCH2OMe (0 °C, 15 min, 79%).10

Other Protection/Deprotection Reactions.

2,6-Lutidine is more effective than Silver(I) Carbonate or other amine bases at mediating the conversion of a 2-acetylpyranosyl bromide to an orthoester (eq 4).11 Side reactions are minimized due to the lower acidity of the conjugate acid of 2,6-lutidine (pKa 6.7) when compared to the other substituted pyridines examined. Exo stereoselectivity is maximized when using 2,6-lutidine rather than silver carbonate. 2,6-Lutidine considerably accelerates bond cleavage during the triarylamine radical cation-mediated oxidative cleavage of primary and secondary benzyl12 and p-methoxybenzyl13 ethers to the corresponding alcohols.

Rosenmund Reduction.

2,6-Lutidine is usefully employed as an HCl scavenger in the catalytic hydrogenation of aliphatic acyl chlorides to aldehydes (Rosenmund reduction) (eq 5).14 These reactions are run in THF at <0.25 M in substrate to prevent poisoning of the Pd catalyst. 2,6-Lutidine is far superior to other basic additives (e.g. Diisopropylethylamine, N,N-dimethylaniline, NaOAc). This method can tolerate ketone and ester functionality, proceeds on both unhindered and crowded acyl chlorides, and is especially suitable for the preparation of sensitive aldehydes. These reactions are faster and superior to those performed under classical Rosenmund reduction conditions (no added base), where high reaction temperatures are required and where the HCl byproduct can mediate side reactions.

Preparation of Boron Enolates.

Dialkylboryl triflates react with ketones in the presence of a hindered tertiary amine base (typically 2,6-lutidine or Diisopropylethylamine) to afford boron enolates that are useful in stereoselective directed aldol condensation reactions.15 2,6-Lutidine is superior to other tertiary amines for the regioselective formation of the more stable 9-BBN boron enolate from alkyl methyl ketones using 9-Borabicyclononyl Trifluoromethanesulfonate (eq 6).15b,16,17 The 2,6-lutidinium triflate byproduct is presumably sufficiently acidic to facilitate enolate equilibration, resulting in thermodynamically controlled enolate formation.15b,17 Interestingly, alkyl ethyl ketones are converted under apparently identical conditions to the less substituted boron enolate18 with relatively high (>10:1) (Z) stereoselectivity (eq 7);17,18 these reactions presumably proceed under kinetic control.17 An opposite sense of regiocontrol has been observed when preparing dibutylboron enolates rather than 9-BBN enolates from alkyl methyl ketones using Di-n-butylboryl Trifluoromethanesulfonate/2,6-lutidine,17 although use of the more hindered and basic diisopropylethylamine in place of 2,6-lutidine affords much higher levels of regiocontrol.17 Poor (Z)-dibutylboron enolate stereoselectivity is observed with alkyl ethyl ketones using 2,6-lutidine under kinetic control;19,20 somewhat improved (>3:1) (Z) selectivity is achieved under thermodynamic control.20 Much higher (Z) stereoselectivity is achieved under strictly kinetic control using diisopropylethylamine as base.17,19,20

Radical Cyclopentannulation Reactions.

Zinc/Chlorotrimethylsilane-mediated cyclopentannulation reactions, involving the addition of an a-siloxy radical to an alkene or alkyne, are best performed in the presence of 2,6-lutidine, which prevents proton and ZnCl2-catalyzed elimination of the tertiary siloxy group in the immediate product (eq 8).21

Oxidation of Allylic Alcohols.

2,6-Lutidine is added to prevent HCl-mediated side reactions during the ruthenium(II)-catalyzed oxidation of allylic alcohols (including labile allylic alcohols such as retinol) to a,b-unsaturated aldehydes using molecular oxygen (eq 9).22 Other less hindered pyridine derivatives poison the catalyst and are ineffective.

Bromination of Sensitive Allylic Alcohols.

Preparation of highly labile allyl bromides can be achieved using Thionyl Bromide/2,6-lutidine (eq 10).23 Virtually no bromide is formed in the absence of 2,6-lutidine.

Related Reagents.

2,4,6-Collidine; 1,5-Diazabicyclo[4.3.0]non-5-ene; 1,8-Diazabicyclo[5.4.0]undec-7-ene; Diisopropylethylamine; Pyridine; Quinoline; Triethylamine.

1. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; pp 212-213.
2. Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. TL 1981, 22, 3455.
3. Tanaka, K.; Yoda, H.; Isobe, Y.; Kaji, A. JOC 1986, 51, 1856.
4. Toshima, K.; Mukaiyama, S.; Kinoshita, M.; Tatsuta, K. TL 1989, 30, 6413.
5. Andrews, R. C.; Teague, S. J.; Meyers, A. I. JACS 1988, 110, 7854.
6. Askin, D.; Angst, C.; Danishefsky, S. JOC 1987, 52, 622.
7. Corey, E. J.; Ensley, H. E. JOC 1973, 38, 3187.
8. Corey, E. J.; Hopkins, P. B. TL 1982, 23, 4871.
9. Furusawa, K.; Ueno, K.; Katsura, T. CL 1990, 97.
10. Matsuda, F.; Kawasaki, M.; Terashima, S. TL 1985, 26, 4639.
11. Mazurek, M.; Perlin, A. S. CJC 1965, 43, 1918.
12. Schmidt, W.; Steckhan, E. AG(E) 1979, 18, 801.
13. Schmidt, W.; Steckhan, E. AG(E) 1978, 17, 673.
14. Burgstahler, A. W.; Weigel, L. O.; Shaefer, C. G. S 1976, 767.
15. (a) Braun, M. In Advances in Carbanion Chemistry; Snieckus, V., Ed.; Jai: Greenwich, CT, 1992; Vol. 1, pp 177-247. (b) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
16. Inoue, T.; Uchimaru, T.; Mukaiyama, T. CL 1977, 153.
17. Inoue, T.; Mukaiyama, T. BCJ 1980, 53, 174.
18. Van Horn, D. E.; Masamune, S. TL 1979, 2229.
19. Evans, D. A.; Vogel, E.; Nelson, J. V. JACS 1979, 101, 6120.
20. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. JACS 1981, 103, 3099.
21. Corey, E. J.; Pyne, S. G. TL 1983, 24, 2821.
22. Matsumoto, M.; Ito, S. CC 1981, 907.
23. Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S. TL 1985, 26, 5239.

Paul Sampson & Thomas E. Janini

Kent State University, OH, USA

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