Cesium Fluoride

CsF

[13400-13-0]  · CsF  · Cesium Fluoride  · (MW 151.90)

(fluoride ion source for removal of silyl protecting groups; reagent for mild desilylative anion and ylide formation; base catalyst; reagent for hydrogen bond-assisted alkylation; reagent for halide exchange)

Physical Data: mp 682 °C; bp 1251 °C; d 4.115 g cm-3; refractive index 1.478 (18 °C).

Solubility: sol H2O and MeOH; insol dioxane, pyridine.

Form Supplied in: white deliquescent crystalline powder.

Purification: dry by heating at 100 °C for 2 h in vacuo.1

Handling, Storage, and Precautions: hygroscopic. Keep container tightly closed. Harmful if inhaled or swallowed. Causes irritation of skin, eyes, and mucous membranes and may cause allergic reaction. Incompatible with acids: store away from acids. Use in a fume hood with safety goggles and chemically resistant gloves and clothing.

Catalysis of Condensations of Carbonyl Compounds.

Knoevenagel condensations of cyclohexanone and benzaldehyde with three active-methylene partners have been studied using various fluoride catalysts. Cesium and rubidium counterions lead to higher yields than the less soluble potassium, sodium, and lithium salts.2 Silyl enol ethers react with aldehydes and ketones with CsF catalysis to form a,b-unsaturated ketones, or with unsaturated ketones by conjugate addition.3 Trimerization of isocyanates occurs at 130 °C with CsF catalysis, forming aromatic isocyanurates in high yields.4

Desilylative Elimination and Carbanion Formation.

Fluoride ion desilylates compounds of the type C-Si, leading to useful carbanion-like reactivity, particularly when appropriate stabilizing substituents are present. When b-substituents are reasonable leaving groups, the expected eliminations occur. These types of reactions, with which water interferes, are particularly amenable to the use of CsF, since CsF can be made anhydrous much easier than the more commonly encountered Tetra-n-butylammonium Fluoride.

Cyclopropenes have been prepared by desilylation of 1,1-dichloro-2-trimethylsilylcyclopropane with CsF in diglyme at 80 °C (eq 1).5 A similar example of an advantage of CsF (and fluoride ion sources in general) - mild elimination conditions allowing isolation of unstable species - is seen in a synthesis of allene oxides. 1-(t-Butyl)allene oxide can be obtained in 55% yield by treating the precursor trimethylsilyloxirane with CsF (eq 2) and trapping the volatile products in a cold trap.6 Desilylative 1,2-elimination from cyclohexadienes has been used to obtain the interesting benzene isomers 1,2,3-cyclohexatriene and cyclohexen-3-yne, which were trapped in situ by Diel-Alder reactions.7 Sulfine, sulfene, and alkylsulfenes can be trapped as Diels-Alder adducts after their generation by desilylative 1,2-elimination from trimethylsilylmethanesulfinyl chloride, trimethylsilylmethanesulfonyl chloride, and trimethylsilylalkanesulfonic anhydrides, respectively.8

CsF-induced 1,4-elimination produces xylylene intermediates which undergo intramolecular cycloaddition with an alkene (eq 3).9 Similar 1,4-elimination/Diels-Alder strategies have been used in the synthesis of other targets,10 and in a cyclodimerization to give the bisthioacetal of [2,3:6,7]dibenzo-1,5-cyclooctanedione.11

Stereoselective synthesis of 1,4-dienamine derivatives is achieved by CsF-induced desilylative ring-opening of tetrahydropyridinium salts. The diene is produced selectively as the (Z,E) diastereomer (eq 4). The authors contrast this behavior with that of an analogous tetrahydropyridine N-oxide, which undergoes spontaneous sila-Cope rearrangement to give the (Z,Z) diastereomer (eq 5).12

Numerous desilylative reactions of trimethyl(a-bromobenzyl)silanes with electrophiles are induced by CsF (eq 6).13

Acyl-, alkynyl-, benzyl-, allyl-, oxiranyl-,14 heteroaryl-,15 trichloromethyl-,16 aryl-,17 b-keto-,18 b-sulfonyl-,19 and cyclopropylsilanes20 are useful carbanion precursors. When treated with CsF or other fluoride salts, they undergo desilylative addition to carbonyl compounds, including CO2, aldehydes, ketones, and lactones; C-alkylation with Benzyl Bromide also can occur (eqs 7-11). Conjugate addition is also observed; nitroalkenes give 1,4-addition products, and reaction of allylsilane with cyclohexenone in the presence of CsF gives the 1,4-addition product selectively, whereas the presence of tetrabutylammonium fluoride leads to diallylated product.21

Cyclization of a carbanion produced by desilylation with CsF leads to 1,3-thiazolidines (eq 12).22

Anionic reactivity remote from the silyl bond cleavage site is observed when ketene bis(trimethylsilyl) acetals or a,b-unsaturated ketene bis(trimethylsilyl) acetals are treated with CsF and an aldehyde.23 Complementary regioselectivity occurs with Titanium(IV) Chloride (eq 13).24

A novel method for the production of thiiranes from carbonyl compounds involves desilylation with CsF (eq 14).25

Stannyl Anion Generation.

By treatment of (trimethylsilyl)tributylstannane with CsF, a stannyl anion is formed. This method was used to achieve intramolecular reaction of a vinyl iodide with an ester, forming a spirocyclopentenone, which reacted further with the tributylstannyl anion under the reaction conditions (eq 15). Four subsequent steps completed a formal total synthesis of acorone.26

Ylide Formation.

Wittig reaction of a phosphonium salt with benzaldehyde is observed with CsF in DMF.27 Similarly, CsF can be used to carry out Horner-Wadsworth-Emmons reactions.28 Sulfonium, ammonium, and phosphonium ylides can be obtained by desilylation.29 This ylide formation strategy has been used in a synthesis of the retronecine skeleton.30

Acylation and Transesterification.

Esters, amides, and thioesters are obtained in high yields under neutral conditions when the carboxylic acid is treated with the appropriate protic nucleophile, 1-ethyl-2-fluoropyridinium tetrafluoroborate, and CsF in methylene chloride (eq 16). p-Nitrophenyl esters of optically pure N-phthaloylamino acids are converted to methyl esters in MeOH/CsF without the racemization observed when triethylamine is employed.31

Acylations of 2,3,4,6-tetra-O-benzyl-D-glucopyranose in quantitative yields are achieved with acyl fluorides and CsF (eq 17). High ratios of either anomeric product can be obtained by changing the order of addition of the reagents.32

.

Phosphate esters can be transesterified in alcohols containing excess CsF.33 This method has been used to advantage in the regioselective protection of hydroquinones by phosphorylation in the presence of CsF.34 Ribooligonucleotides have also been synthesized by this approach.35

Acylation of alcohols is very efficient with acylthiazolidine-2-thiones and CsF in warm DMF. Benzyl 3-phenylpropionate was obtained in 99% yield by this method (eq 18).36

Hydrogen Bond-Assisted Halide Displacements.

Treatment of catechols with CH2Cl2 in the presence of CsF results in high yields of methylenated products (eq 19) with little competition from intermolecular condensations.37 Hydrogen bonding of the catechol with fluoride has been demonstrated, and is thought to be responsible for the facilitation of the reaction. Numerous other H-bonding substrates are also alkylated more readily under the influence of fluoride (eq 20).38 This alkylation promotion by CsF obviates prior conversion of phthalimide to its alkali metal derivative for use in the Gabriel synthesis (eq 21).39 CsF leads to an order of magnitude in rate enhancement relative to Potassium Fluoride in some cases, although the higher expense of CsF may negate this advantage.

1,2-Cycloalkanediols can also be methylenated under analogous conditions.40 Glycols can be monoalkylated by treatment of their stannylene acetals with alkyl halides. CsF considerably improves the yields of these reactions.41 Thus the dibutylstannylene acetal of dimethyl L-tartrate was monoalkylated with benzyl iodide and CsF in DMF at room temperature in 99% yield (eq 22), whereas the reaction without CsF required elevated temperatures and gave only a 13% yield. This method has recently been applied in syntheses of lepidimoide42 and myo-inositol phosphates.43 In a related reaction, glycol xanthates react with alcohols in the presence of CsF to provide monoalkylated glycols as a key step in syntheses of xylofuranosides.44 Phosphoric acid alkylation by alkyl halides is catalyzed by CsF.45 Several macrocyclic crown ethers have been prepared by reaction of ditosylated half-crowns with diol half-crowns in the presence of CsF.46

Synthesis of Acid Fluorides.

Organic halides can be converted to acid fluorides by metal-catalyzed (M = Pd, Pt, Co, Rh) carbonylation in the presence of fluoride salts (eq 23). CsF is superior to fluorides with other counterions.47

Preparation of Alumina-Supported Fluoride Reagents.

Mixing of aqueous CsF or KF with alumina followed by drying gave an effective base catalyst.48 Its preparation was optimized by testing the activity in promoting Michael addition of nitroethane to buten-2-one and methylation of phenols with MeI.

Activation of Si-X Bonds.

Silicon-hydrogen, -oxygen, and -nitrogen bonds are activated by fluoride ions under heterogeneous conditions. Triethoxysilane is a mild, efficient and highly selective reducing agent in the presence of CsF, leading to quantitative yields of 1,2-reduction products from enones (eq 24). Other bifunctional compounds also can be reduced with quantitative regioselectivity.49

A system of CsF and Si(OR)4 effects selective 1,4-addition in condensation of ketones with activated alkenes in good yield (eq 25). A silyl enol ether is formed in situ via reaction of CsF-activated Si(OR)4 with the ketone.49 This system has also been used to effect 1,4-addition to unsaturated amides.50 Although bis(silyl)enamines undergo sluggish reaction, if any, with various electrophiles, the presence of CsF or tributylammonium fluoride allows high-yielding reactions with carbonyl compounds to afford 2-aza-1,3-dienes (eq 26).51

Benzostabase Protecting Group.

Aromatic and aliphatic primary amines have been protected as their benzostabase derivatives in high yield by heating with 1,2-bis(dimethylsilyl)benzene and CsF in polar aprotic solvents (eq 27).52

Desilylation of O-Silyl and N-Silyl Compounds.

O-Silyl compounds serve frequently as protecting functionalities in organic synthesis. CsF is sometimes used for cleavage of these Si-O bonds, but usually has no advantage over the more commonly used tetrabutylammonium fluoride. Cleavage of O-Si bonds with CsF has been used in the preparation of cesium selenocarboxylates.53 CsF can be used to cleave N-trimethylsilyl groups from amides54 and carbodiimides.55

Fluorodemetalation of Organogermanium, -tin, -lead, and -boron Compounds.

Cesium fluoride can be used to cleave C-M bonds; evidence for an associative mechanism in this process has been obtained.56 Similar reactivity is observed in the reaction of organotin carboxylates and stannyl ethers with CsF and alkyl halides; the O-Sn bond is converted to O-C.57 A borane-amine complex has been decomposed to the free amine by refluxing with CsF in Na2CO3/EtOH.58

CsF-Mediated Claisen Rearrangement.

Aryl propargyl ether Claisen rearrangement leads to an intermediate allene which undergoes intramolecular capture by the concurrently formed phenol to give a pyran or a furan. A comparison of the effects of various salts on the regioselectivity revealed that CsF promotes the furan formation, despite the fact that both CsCl and KF promote pyran formation. The reaction also was applied in a synthesis of chelerythrine (eq 28).59

Alkyl Fluoride Synthesis.

n-Octyl fluoride has been made in 77% yield (along with 15% of n-octane) by treatment of n-octyl bromide with CsF and catalytic NBu4Br at 85 °C.60

Related Reagents.

Diphenylsilane-Cesium Fluoride; Phenylsilane-Cesium Fluoride; (Trimethylsilyl)methanesulfonyl Chloride-Cesium Fluoride.


1. Corriu, R. J. P.; Moreau, J. J. E.; Pataud-Sat, M. JOC 1990, 55, 2878.
2. Rand, L.; Swisher, J. V.; Cronin, C. J. JOC 1962, 27, 3505.
3. Boyer, J.; Corriu, R. J. P.; Perz, R.; Reye, C. JOM 1980, 184, 157.
4. Nambu, Y.; Endo, T. JOC 1993, 58, 1932.
5. Chan, T. H.; Massuda, D. TL 1975, 3383.
6. Chan, T. H.; Ong, B. S. JOC 1978, 43, 2994.
7. Shakespeare, W. C.; Johnson, R. P. JACS 1990, 112, 8578.
8. (a) Block, E.; Aslam, M. TL 1982, 23, 4203. (b) Block, E.; Wall, A. TL 1985, 26, 1425.
9. Ito, Y.; Nakatsuka, M.; Saegusa, T. JACS 1981, 103, 476.
10. (a) Djuric, S.; Sarkar, T.; Magnus, P. JACS 1980, 102, 6885. (b) Marino, J. P.; Dax, S. L. JOC 1984, 49, 3671. (c) Ito, Y.; Miyata, M.; Nakatsuka, M.; Saegusa, T. JACS 1981, 103, 5250.
11. Ito, Y.; Nakajo, E.; Sho, K.; Saegusa, T. S 1985, 698.
12. Bac, N. V.; Langlois, Y. JACS 1982, 104, 7666.
13. Kessar, S. V.; Singh, P.; Kaur, N. P.; Chawla, U.; Shukla, K.; Aggarwal, P.; Venugopal, D. JOC 1991, 56, 3908.
14. Ricci, A.; Fiorenza, M.; Grifagni, M. A.; Bartolini, G.; Seconi, G. TL 1982, 23, 5079; and references therein.
15. Effenberger, F.; Spiegler, W. CB 1985, 118, 3872.
16. Cunico, R. F.; Zhang, C. SC 1991, 21, 2189.
17. Mills, R. J.; Snieckus, V. JOC 1989, 54, 4386.
18. Fiorenza, M.; Mordini, A.; Papaleo, S.; Pastorelli, S.; Ricci, A. TL 1985, 26, 787.
19. Eisch, J. J.; Behrooz, M.; Dua, S. K. JOM 1985, 285, 121.
20. (a) Ohno, M.; Tanaka, H.; Komatsu, M.; Ohshiro, Y. SL 1991, 919. (b) Blankenship, C.; Wells, G. J.; Paquette, L. A. T 1988, 44, 4023. (c) Paquette, L. A.; Blankenship, C.; Wells, G. J. JACS 1984, 106, 6442.
21. Ricci, A.; Fiorenza, M.; Grifagni, M. A.; Bartolini, G.; Seconi, G. TL 1982, 23, 5079.
22. Hosomi, A.; Hayashi, S.; Hoashi, K.; Kohra, S.; Tominaga, Y. JOC 1987, 52, 4423.
23. Bellassoued, M.; Gaudemar, M. TL 1988, 29, 4551.
24. Bellassoued, M.; Ennigrou, R.; Gaudemar, M. JOM 1990, 393, 19.
25. Tominaga, Y.; Ueda, H.; Ogata, K.; Kohra, S.; Hojo, M.; Ohkuma, M.; Tomita, K.; Hosomi, A. TL 1992, 33, 85.
26. Mori, M.; Isono, N.; Kaneta, N.; Shibasaki, M. JOC 1993, 58, 2972.
27. Umemoto, T.; Gotoh, Y. BCJ 1991, 64, 2008.
28. Kawashima, T.; Ishii, T.; Inamoto, N. BCJ 1987, 60, 1831.
29. (a) Vedejs, E.; Martinez, G. R. JACS 1979, 101, 6452. (b) Machida, Y.; Shirai, N.; Sato, Y. S 1991, 117.
30. Vedejs, E.; West, F. G. JOC 1983, 48, 4773.
31. Shoda, S.; Mukaiyama, T. CL 1980, 391.
32. Shoda, S.; Mukaiyama, T. CL 1982, 861.
33. (a) Ogilvie, K. K.; Beaucage, S. L. CC 1976, 443. (b) Ogilvie, K. K.; Beaucage, S. L.; Theriault, N.; Entwistle, D. W. JACS 1977, 99, 1277.
34. Duthaler, R. O.; Lyle, P. A.; Heuberger, C. HCA 1984, 67, 1406.
35. Takaku, H.; Nomoto, T.; Murata, M.; Hata, T. CL 1980, 1419.
36. Yamada, M.; Yahiro, S.; Yamano, T.; Nakatani, Y.; Ourisson, G. BSF 1990, 824.
37. Clark, J. H.; Holland, H. L.; Miller, J. M. TL 1976, 3361.
38. Clark, J. H.; Miller, J. M. TL 1977, 599.
39. Clark, J. H. and Miller, J. M. JACS 1977, 99, 498.
40. Hagenbuch, J.-P.; Vogel, P. C 1977, 31, 136.
41. Nagashima, N.; Ohno, M. CL 1987, 141.
42. Kosemura, S.; Yamamura, S.; Kakuta, H.; Mizutani, J.; Hasegawa, K. TL 1993, 34, 2653.
43. Yu, K.-L.; Fraser-Reid, B. TL 1988, 29, 979.
44. Murakami, M.; Mukaiyama, T. CL 1983, 1733.
45. Takaku, H.; Kamaike, K.; Mori, H.; Ishido, Y. CPB 1983, 31, 2157.
46. deBoer, J. A. A.; Uiterwijk, J. W. H. M.; Geevers, J.; Harkema, S.; Reinhoudt, D. N. JOC 1983, 48, 4821.
47. Sakakura, T.; Chaisupakitsin, M.; Hayashi, T.; Tanaka, M. JOM 1987, 334, 205.
48. Ando, T.; Brown, S. J.; Clark, J. H.; Cork, D. G.; Hanafusa, T.; Ichihara, J.; Miller, J. M.; Robertson, M. S. JCS(P2) 1986, 1133.
49. Corriu, R. J. P.; Perz, R.; Reye, C. T 1983, 39, 999.
50. (a) Chuit, C.; Corriu, R. J. P.; Perz, R.; Reye, C. T 1986, 42, 2293. (b) Corriu, R. J. P.; Perz, R. TL 1985, 26, 1311.
51. Corriu, R. J. P.; Moreau, J. J. E.; Pataud-Sat, M. JOC 1990, 55, 2878.
52. (a) Bonar-Law, R. P.; Davis, A. P.; Dorgan, B. J.; Reetz, M. T.; Wehrsig, A. TL 1990, 31, 6725. (b) Bonar-Law, R. P.; Davis, A. P.; Dorgan, B. J. TL 1990, 31, 6721.
53. Kawahara, Y.; Kato, S.; Kanda, T.; Murai, T.; Ishihara, H. CC 1993, 277.
54. Kawaguchi, M.; Hamaoka, S.; Mori, M. TL 1993, 34, 6907.
55. Aumüller, A.; Hünig, S. AG(E) 1984, 23, 447.
56. Gingras, M.; Chan, T. H.; Harpp, D. N. JOC 1990, 55, 2078.
57. (a) Sato, T.; Otera, J.; Nozaki, H. JOC 1992, 57, 2166. (b) Sato, T.; Tada, T.; Otera, J.; Nozaki, H. TL 1989, 30, 1665. See also: Gingras, M.; Chan, T. H.; Harpp, D. N. JOC 1990, 55, 2078.
58. Macor, J. E.; Newman, M. E. TL 1991, 32, 3345.
59. Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M.; Harayama, T. CPB 1990, 38, 1775.
60. Bram, G.; Loupy, A.; Pigeon, P. SC 1988, 18, 1661.

Gregory K. Friestad & Bruce P. Branchaud

University of Oregon, Eugene, OR, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.