n-Butyllithium-Boron Trifluoride Etherate1


[109-72-8]  · C4H9Li  · n-Butyllithium-Boron Trifluoride Etherate  · (MW 64.06) (BF3.OEt2)

[109-63-7]  · C4H10BF3O  · n-Butyllithium-Boron Trifluoride Etherate  · (MW 141.93)

(Lewis acid catalyst/strong base combination used to simultaneously generate an anion and activate an electrophile at low temperature, i.e. double activation2)

Physical Data: see n-Butyllithium and Boron Trifluoride Etherate.

Form Supplied in: the reagents are mixed with reactants in situ. BF3.OEt2 is supplied as a purified, redistilled liquid. n-Butyllithium is available as a 2 M solution in cyclohexane, 1.6 M, 2.5 M, and 10 M solution in hexanes, and a 2 M solution in pentane.

Handling, Storage, and Precautions: BF3.OEt2 is a fuming, corrosive liquid and is immediately hydrolyzed by moisture in air; n-butyllithium solutions are moisture sensitive and pyrophoric. Accordingly, both reagents should be stored and handled in the absence of moisture under N2.3

Alkynyllithium Reagents and BF3.OEt2.

The most common use of the n-BuLi/BF3.OEt2 reagent combination is in the formation of lithium acetylides from terminal alkynes and their subsequent addition to a variety of electrophiles. While boron halides (BX3) undergo rapid displacement with organolithiums (RLi) to furnish alkylhaloboranes (RBX2 and R2BX) and trisubstituted boranes (R3B) at ambient temperatures,4 it has been determined that organolithiums and BF3.OEt2 are stable together at low temperature and react independently.5 Moreover, addition of BF3.OEt2 to lithium acetylides at -78 °C in THF affords an intermediate, lithium alkynyltrifluoroborate complex (1) (eq 1), which reacts smoothly with carboxylic acid anhydrides,6 esters,7 and tertiary amides8 to give a,b-alkynic ketones in high yields (eqs 2-4). The acetylide-amide coupling can also be used with a subsequent Lithium Aluminum Hydride reduction to afford azacycloalkanes (eq 5).8d

It has also been found that this complex cleaves epoxides to afford b-hydroxyalkynes in excellent yields (eq 6);9 this method has been used extensively, as seen in the syntheses of FK 506,10 okadaic acid,11 lipoxin B,12 N-acetylactinobolamine,13 and leukotriene B4.14 The use of other metal acetylides for this transformation requires longer reaction times, higher temperatures and/or expensive catalysts, frequently resulting in low yields. Reaction of borate complex (1) (R = Ph) with (2S,3S)-3-phenylglycidol gave diol (2) with >99:1 diastereoselectivity, whereas the diethylaluminate complex afforded a 3:1 mixture (eq 7).15 Borate complex (1) can also be used in the ring opening of oxetanes to give g-hydroxyalkynes (eq 8).16

Borate complex (1; R = CH2OTr) has also been added to an a-diazo ester to give a b,g-alkynic ester as well as to an a-hydroxyaldehyde (1; R = CMe2OTHP) to afford an a,b-dihydroxyalkyne.17,18

Lithium Enolates and Stabilized Alkyllithiums with BF3.OEt2.

The mechanisms by which BF3.OEt2 activates most of the following reactions remain unclear; while coordination of the Lewis acid with certain electrophiles prior to nucleophilic addition has been reported,5 the possibility of BF3/organolithium complexes cannot be precluded in all cases. It has been shown that the lithium enolates of amides19 will cleave epoxides in the presence of BF3.OEt2 to afford g-hydroxyamides, while the lithium enolates of both amides and esters will open oxetanes to give d-hydroxy esters and d-hydroxyamides in high yield (eq 9).20 It was found that the lithium enolate of optically active iron acyl (4) would cleave trans-(±)-2,3-epoxybutane at -78 °C to afford g-hydroxy product (5) as a 10:1 mixture of diastereomers (eq 10);21 the enantiofacial recognition of this reaction allows for the synthesis of optically active b,g-dimethyl-g-lactones.

It also has been shown that the lithium enolates of ketones and esters can be added to BF3.OEt2-activated 3-thiazolines to give functionalized thiazolidines22a and trisubstituted thiophenes;22b lithium enolates of ketones can also be dialkoxymethylated using orthoformates in this manner.23 In the presence of BF3.OEt2 the sodium-lithium dianion of b-keto esters will react with disubstituted epoxides to give tetrahydrofurans after acid-promoted cyclization,24 as well as undergo Claisen condensations with tertiary amides.25

Concerning other stabilized organolithiums, a-lithiated sulfones can be treated with BF3.OEt2 activated aldehydes to afford trans-alkenes after reduction (Julia alkenation);26 in addition, treatment with activated epoxides gives g-hydroxy sulfones (eq 11) and a,b-unsaturated ketones after oxidation-elimination.27 In the absence of BF3.OEt2 these processes suffer from low yields and/or long reaction times. In a separate example, it was found that when lithiated 2-styryl-1,3-dithiane was treated with aldehydes and ketones, a mixture of alcohols (6) and (7) would result (eq 12); however, treatment of the dithiane anion with BF3.OEt2 prior to the addition of carbonyl compound resulted in exclusive a-addition to give alcohol (7).28

Other examples of reactions of stabilized organolithiums with BF3.OEt2 activation include the cleavage of a monosubstituted epoxide with an a-lithiophosphonate,29 the addition of a-lithiated sulfoximines30 to aldehydes and imines, and the cleavage of oxetanes with lithiomethylphosphonates (eq 13).31

Nonstabilized Organolithiums with BF3.OEt2.

By far the most common reaction of nonstabilized organolithiums with BF3.OEt2 activation is the cleavage of epoxides. Examples include alkyl-, alkenyl-, and aryllithiums in both intra- and intermolecular variations; the mechanism of these reactions appears to include complexation of the Lewis acid at oxygen followed by nucleophilic attack of the carbon nucleophile on the resulting alkoxyboron trifluoride salt.5 The organolithium reagents used include commercial reagents (Methyllithium, s-Butyllithium, n-Butyllithium, t-Butyllithium, Phenyllithium) as well as those prepared from alkylstannanes, alkenyl halides, aryl halides, furans, and indoles.

In one example it was found that in the presence of BF3.OEt2, diepoxide (8) could be treated with an excess of alkyl- and aryllithiums to afford symmetric 1,3-diols; more importantly, 1 equiv of organolithium reagent could be used to give C(2) differentiated epoxy alcohols which could be further elaborated with a second organolithium species (eqs 14 and 15).32

While vinyllithium reagents will cleave epoxides in good yields, a threefold excess of the reagent is required; it has been reported that this shortcoming can be avoided by the conversion of the lithium reagent to the corresponding alkenylaluminum species (see Diethylaluminum Chloride) which will react smoothly under stoichiometric conditions in the presence of BF3.OEt2 to afford homoallylic alcohols in good yields.33 Oxetanes are also cleaved by organolithium-BF3 reagents.5

Other reactions of organolithiums utilizing BF3.OEt2 include those with: alkyl/aryllithiums and oxime ethers to give substituted O-alkyl hydroxylamines;34 alkyl/aryllithiums and 2-isoxazolines to afford substituted isoxazolidines;35 butenolide anions and orthoesters to give acylated butenolides;2 alkyllithiums and imines to give a-alkylated amines;36 an allenic zirconium species and aldehydes to afford b-alkynic alcohols;37 and alkyllithiums with aldehydes/ketones to afford alcohols.38

1. Yamamoto, Y. AG(E) 1986, 25, 947.
2. Pelter, A.; Al-Bayati, R. TL 1982, 23, 5229.
3. Gill, G. B.; Whiting, D. A. Aldrichim. Acta 1986, 19, 31.
4. (a) Niedenzu, K. Organomet. Chem. Rev. 1966, 1, 305. (b) For a more recent example, see: Wilkey, J. D.; Schuster, G. B. JOC 1987, 52, 2117.
5. Eis, M. J.; Wrobel, J. E.; Ganem, B. JACS 1984, 106, 3693.
6. Brown, H. C.; Racherla, U. S.; Singh, S. M. TL 1984, 25, 2411.
7. (a) Yamaguchi, M.; Shibato, K.; Fujiwara, S.; Hirao, I. S 1986, 421. (b) For additional examples, see: Linderman, R. J.; Lonikar, M. S. JOC 1988, 53, 6013.
8. This procedure requires a three-fold excess of acetylide to amide: (a) Yamaguchi, M.; Waseda, T.; Hirao, I. CL 1983, 35. (b) For use in a total synthesis, see: Barrish, J. C.; Lee, H. L.; Mitt, T.; Pizzolato, G.; Baggiolini, E. G.; Uskokovic, M. R. JOC 1988, 53, 4282. (c) For use with amino acid derivatives, see: Cupps, T. L.; Boutin, R. H.; Rapoport, H. JOC 1985, 50, 3972. (d) Yamaguchi, M.; Hirao, I. TL 1983, 24, 1719. (e) If (triphenylsilyl)acetylide is used, enaminones result; see: Suzuki, K.; Ohkuma, T.; Tsuchihashi, G. JOC 1987, 52, 2929.
9. Yamaguchi, M.; Hirao, I. TL 1983, 24, 391.
10. Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. JACS 1990, 112, 5583.
11. Ichikawa, Y.; Isobe, M.; Bai, D.-L.; Goto, T. T 1987, 43, 4737.
12. Morris, J.; Wishka, D. G. TL 1986, 27, 803.
13. Askin, D.; Angst, C.; Danishefsky, S. JOC 1987, 52, 622.
14. Merrer, Y. L.; Gravier-Pelletier, C.; Micas-Languin, D.; Mestre, F.; Dureault, A.; Depezay, J.-C. JOC 1989, 54, 2409.
15. Takano, S.; Yanase, M.; Ogasawara, K. H 1989, 29, 249.
16. (a) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. T 1984, 40, 4261. (b) Kurek-Tyrlik, A.; Wicha, J.; Zarecki, A.; Snatzke, G. JOC 1990, 55, 3484.
17. Yasukouchi, T.; Kanematsu, K. TL 1989, 30, 6559.
18. Dolence, E. K.; Adamczyk, M.; Watt, D. S.; Russell, G. B.; Horn, D. H. S. TL 1985, 26, 1189.
19. Takahata, H.; Takamatsu, T.; Yamazaki, T. JOC 1989, 54, 4812.
20. Yamaguchi, M.; Shibato, K.; Hirao, I. TL 1984, 25, 1159.
21. (a) Davies, S. G.; Middlemiss, D.; Naylor, A.; Wills, M. TL 1989, 30, 587. (b) For a second example of this reaction, see: Ojima, I.; Kwon, H. B. JACS 1988, 110, 5617. (c) For an example of this reaction using a chromium carbene complex, see: Lattuada, L.; Licandro, E.; Maiorana, S.; Molinari, H.; Papagni, A. OM 1991, 10, 807. (d) For an example of a chromium carbene enolate with an aldehyde/BF3.OEt2, see: Wulff, W. D.; Gilbertson, S. R. JACS 1985, 107, 503.
22. (a) Meltz, C. N.; Volkmann, R. A. TL 1983, 24, 4503. (b) Meltz, C. N.; Volkmann, R. A. TL 1983, 24, 4507.
23. Suzuki, M.; Yanagisawa, A.; Noyori, R. TL 1982, 23, 3595.
24. Lygo, B.; O'Connor, N.; Wilson, P. R. T 1988, 44, 6881.
25. Yamaguchi, M.; Shibato, K.; Nakashima, H.; Minami, T. T 1988, 44, 4767.
26. (a) Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankowski, J.; Wicha, J. T 1988, 44, 4989. (b) For use in a total synthesis, see: Schreiber, S. L.; Meyers, H. V. JACS 1988, 110, 5198.
27. (a) Marczak, S.; Wicha, J. SC 1990, 20, 1511. (b) Nakata, T.; Saito, K.; Oishi, T. TL 1986, 27, 6345.
28. Fang, J.-M.; Chen, M.-Y.; Yang, W.-J. TL 1988, 29, 5937.
29. Bittman, R.; Byun, H.-S.; Mercier, B.; Salari, H. JMC 1993, 36, 297.
30. Pyne, S. G.; Dikic, B.; Skelton, B. W.; White, A. H. AJC 1992, 45, 807.
31. Tanaka, H.; Fukui, M.; Haraguchi, K.; Masaki, M.; Miyasaka, T. TL 1989, 30, 2567.
32. Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. JOC 1991, 56, 5161.
33. Alexakis, A.; Jachiet, D. T 1989, 45, 6197.
34. (a) Uno, H.; Terakawa, T.; Suzuki, H. SL 1991, 559. (b) Rodriques, K. E.; Basha, A.; Summers, J. B.; Brooks, D. W. TL 1988, 29, 3455.
35. Uno, H.; Terakawa, T.; Suzuki, H. CL 1989, 1079.
36. Muratake, H.; Natsume, M. H 1985, 23, 1111.
37. Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y. TL 1992, 33, 3769.
38. Singh, S. M.; Oehlschlager, A. C. CJC 1988, 66, 209.

Michael L. Curtin

Abbott Laboratories, Abbott Park, IL, USA

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