Tri-n-butylphosphine

Bu3P

[998-40-3]  · C12H27P  · Tri-n-butylphosphine  · (MW 202.36)

(1,4-addition catalyst; used with disulfides for the thioetherification of alcohols; acylation catalyst; used to prepare active esters)

Physical Data: bp 240 °C; bp 130 °C/20 mmHg; d 0.812 g cm-3.

Solubility: sol most organic solvents; slightly sol MeCN, H2O.

Form Supplied in: widely available, neat; usually requires distillation.

Analysis of Reagent Purity: 31P NMR.1

Purification: distillation at reduced pressure. Improperly stored bottles of Bu3P are invariably contaminated with tributylphosphine oxide and butyl dibutylphosphinate.

Handling, Storage, and Precautions: can be stored at room temperature indefinitely under an inert atmosphere. Oxygen should be rigorously excluded to avoid free radical chain oxidation. Tributylphosphine is pyrophoric and has an unpleasant odor. Toxicity: LD50 (rat) 750 mg kg-1.2

Introduction.

Of the commonly used tertiary phosphines, tributylphosphine3 is exceptionally nucleophilic. It is a relatively weak base (pKa 8.70 in MeNO2, 5.60 in MeOH)4 and rather stable to atmospheric oxidation, surviving for days in nondegassed solvents under nitrogen. Exposure to O2 results in radical oxidation, giving mixtures of Bu2P(O)OBu and Bu3PO in variable ratios, depending on the solvent.5

Thioetherification.

Tributylphosphine reacts with disulfides and alcohols to give the corresponding thioethers and Bu3PO. This mild procedure was first used to prepare nucleoside thioethers (eq 1).6 The activation step is similar to that used in the synthesis of peptides with Triphenylphosphine/2,2-Dipyridyl Disulfide,7 and is conceptually related to the Mitsunobu activation method. This protocol has been used effectively in the synthesis of complex small molecules.8 In some synthetic applications, thioetherification is followed by oxidation (m-Chloroperbenzoic Acid) and elimination (0 °C) to obtain the alkene.9

The thioetherification of diols occurs with remarkable chemoselectivity: Diphenyl Disulfide/Bu3P (Hata reagent) can distinguish between primary and secondary neopentyl alcohols.10 Activation of allylic alcohols by the Hata reagent results in partial allylic transposition, giving ca. 2:1 mixtures of isomers (eq 2).11 Thiophenylsuccinimides have also been employed in the preparation of phenyl thioethers.12

Thio- and selenoetherification is believed to proceed with inversion of configuration at the reacting center. In accord with this presumption, chiral secondary alcohols react with phenyl selenocyanates and Bu3P, undergoing 93-96% inversion to the phenyl selenoethers.13 The fidelity of the inversion may be subject to the same electronic factors which affect the Mitsunobu activation of ionization-prone alcohols.14

Activated Esters.

Aryl thio- and selenocyanates react with freshly distilled Bu3P and carboxylic acids to give thiol- and selenolesters,15 which can be isolated, or reacted in situ with amines (eq 3). The resulting amides are obtained in high yields with the Grieco reagent, although the method fails for the preparation of large ring lactams.16 Analogously, carboxylic acids react with Diphenyl Diselenide/Bu3P to give activated selenolesters, which are used in the synthesis of peptides.17

Acylation Catalyst.

Tributylphosphine has been used as a nucleophilic acylation catalyst.18 Acetylation and benzoylation of hindered secondary and tertiary alcohols with Acetic Anhydride and Benzoic Anhydride in the presence of 0.1 equiv of Bu3P occurs in high yield with or without added base. In some applications, catalytic rate accelerations match those of 4-Dimethylaminopyridine (DMAP). The Bu3P/Ac2O reagent may prove to be a nonbasic alternative to DMAP and might be utilized in situations where DMAP fails or gives significant side reactions. The use of Bu3P as a nucleophilic catalyst has been extended to a wide variety of substrates.19

1,4-Addition Catalyst.

Tributylphosphine has been most widely used as a 1,4-addition catalyst.20 Although arylalkylphosphines and triphenylphosphine have been used in this application, Bu3P is markedly superior due to its pronounced nucleophilicity (eq 4).21 Amines fail to catalyze the reaction, and because phosphines are less basic (thus unable to deprotonate the nitroalkane), nucleophilic catalysis has been inferred. The yields correlate with phosphine nucleophilicity. The problem of monoalkylation of gramine-derived 3-methyleneindoline species with nitroalkanes has been solved using Bu3P.22 The authors observe no reaction in the absence of Bu3P and speculate that the intermediacy of PV may account for the selectivity observed. Recently, this method has been applied in the synthesis of (+)-paraherquamide (eq 5).23 Interestingly, demethoxycarbonylation of the carbamate also occurs.

The Bu3P-catalyzed 1,4-addition of alcohols to ynoates has recently been reported.24 In addition to short reaction times (10 min vs. 8 h with Ph3P), tributylphosphine gives enhanced (E)/(Z) ratios (99:1 vs 5:1 with Ph3P) in the resulting 3-benzyloxy enoates. Tributylphosphine also catalyzes the ring opening of cyclobutenones.25 Presumably, initial 1,4-addition is followed by electrocyclic ring opening. The crystalline tricyclohexylphosphine has been used to initiate (by 1,4-addition) an Ireland ester enolate Claisen rearrangement,26 and Triphenylphosphine (or Bu3P) isomerizes alkynones to the all-trans dienones.27 Tributylphosphine has been utilized in aqueous systems (pKa 8.43 in H2O).28

Tributylphosphine can intercept p-allyl palladium complexes to yield allylic phosphonium salts, which have been deprotonated and used in Wittig alkenation of aldehydes.29 The use of Bu3P shows improved (E) selectivities over Ph3P, and does not isomerize the alkene geometry of the allylic starting material. In these examples, the role of tributylphosphine extends well beyond that of ancillary ligand.30

Mitsunobu Reaction.31

Different selectivities have been obtained using Bu3P rather than Ph3P in the Mitsunobu reaction.32 In one case, Bu3P gives retention of configuration whereas Ph3P shows (normal)31 inversion of alcohol configuration.33 Although a complete mechanistic picture is as yet unclear, recent studies suggest a more reactive Bu3P/Diethyl Azodicarboxylate (DEAD) reagent. 31P NMR monitoring of the Bu3P/DEAD/ROH reaction shows the presence of an alkoxyphosphonium species instead of the derived phosphorane which is observed with Ph3P.34 Furthermore, the Bu3P-derived betaine reacts faster with nucleophiles than the Ph3P-derived betaine, which has synthetic implications for the order of addition of reagents (e.g. Bu3P, DEAD, ROH, then RCO2H).28 Premature addition of the carboxylic acid component results in symmetrical anhydride formation, which may explain some of the poor yields reported using Bu3P. A more reactive Mitsunobu reagent, comprised of Bu3P and 1,1-(Azodicarbonyl)dipiperidine, has been described.35

Miscellaneous.

The synthesis of O-silyl cyanohydrins by the 1,2-addition of Cyanotrimethylsilane to aldehydes benefits from tributylphosphine catalysis.36 In the reaction of TMSCN with hydrocinnamaldehyde, Bu3P gives the best yield (eq 6). In a hindered intramolecular example of the aza-Wittig reaction, Ph3P fails to give any product but Bu3P gives moderate yields of the desired 1,4-benzodiazepin-5-ones.37


1. 31P NMR (CDCl3, rt, relative to external H3PO4): d -32.1 (Bu3P); d 47.3 (Bu2P(O)OBu); d 56.2 (Bu3P=O). Diver, S. T., unpublished results, 1993.
2. Registry of Toxic Effects of Chemical Substances; Sweet, D. V., Ed.; US Government Printing Office: Washington, 1988; p 3336.
3. (a) Kosolapoff, G. M.; Maier, L. Organic Phosphorus Compounds; Wiley: New York, 1972; Vol. 1, pp 127-128. (b) Edmundson, R. S. Dictionary of Organophosphorus Compounds; Chapman and Hall: London, 1988; pp 794-795.
4. (a) Williams, J. L. CI(L) 1957, 235. (b) Streuli, C. A. Anal. Chem. 1960, 32, 985.
5. Buckler, S. A. JACS 1962, 84, 3093.
6. (a) Nagagawa, I.; Hata, T. TL 1975, 1409. (b) Hata, T.; Sekine, M. CL 1974, 837.
7. Mukaiyama, T.; Matsueda, R.; Suzuki, M. TL 1970, 1901.
8. (a) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D.; Wilhelm, R. S.; Williams, P. D. JACS 1989, 111, 8957. (b) Poli, G.; Belvisi, L.; Manzoni, L.; Scolastico, C. JOC 1993, 58, 3165. (c) Kotsuki, H.; Matsumoto, K.; Nishizawa, H. TL 1991, 32, 4155.
9. Crimmins, M. T.; Jung, D. K.; Gray, J. L. JACS 1993, 115, 3146.
10. Cleary, D. G. SC 1989, 19, 737.
11. Cohen, T.; Abraham, W. D. JACS 1991, 113, 2313.
12. Paquette, L. A.; Meister, P. G.; Friedrich, D.; Sauer, D. R. JACS 1993, 115, 49.
13. Sevrin, M.; Krief, A. CC 1980, 656.
14. Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D. TL 1993, 34, 1195.
15. Grieco, P. A.; Yokoyama, Y.; Williams, E. JOC 1978, 43, 1283.
16. Grieco, P. A.; Clark, D. S.; Withers, G. P. JOC 1979, 44, 2945.
17. Singh, U.; Ghosh, S.; Chadha, M. S.; Mamdapur, V. R. TL 1991, 32, 255. Use of a related PhSSPh/R3P system: Shelykh, G. I.; Vlasov, G. P.; Mitin, Y. V. ZOB 1973, 43, 369 (Engl. Transl.: p 367).
18. Vedejs, E.; Diver, S. T. JACS 1993, 115, 3358.
19. Vedejs, E.: Bennett, N. B.; Conn, L.; Diver, S. T.; Gingras, M.; Lin, S.; Oliver, P. A.; Peterson, M. J. JOC 1993, 58, 7286.
20. Rauhut, M. M.; Currier, H. U.S. Patent 3 074 999, 1963.
21. White, D. A.; Baizer, M. M. TL 1973, 3597.
22. Somei, M.; Karasawa, Y.; Kaneko, C. H 1981, 16, 941.
23. Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. D. JACS 1993, 115, 9323.
24. Inanaga, J.; Baba, Y.; Hanamoto, T. CL 1993, 241.
25. Cammers-Goodwin, A. JOC 1993, 58, 7619.
26. Hanamoto, T.; Baba, Y.; Inanaga, J. JOC 1993, 58, 299.
27. Trost, B. A.; Kazmaier, U. JACS 1992, 114, 7933.
28. (a) Vela, M. A.; Kohn, H. JOC 1992, 57, 6650. (b) See Ref. 4(b).
29. (a) Tamura, R.; Kato, M.; Saegusa, K.; Kakihana, M.; Oda, D. JOC 1987, 52, 4121. (b) Okukado, N.; Uchikawa, O.; Nakamura, Y. CL 1988, 52, 1449.
30. The role of Bu3P in organocopper and organopalladium chemistry as an ancillary ligand should not be understated, however. Recent lead references: (a) Riecke, R.; Stack, D. E.; Dawson, B. T.; Wu, T.-C. JOC 1993, 58, 2483. (b) Mandai, T.; Matsumoto, T.; Tsuji, J.; Saito, S. TL 1993, 34, 2513.
31. Hughes, D. L. OR 1992, 42, 335.
32. Mitsunobu, O. S 1981, 1.
33. Kodaka, M.; Tomohiro, T.; Okuno, H. CC 1993, 81.
34. Camp, D.; Jenkins, I. D. AJC 1992, 45, 47.
35. Tsunoda, T.; Yamamiya, Y.; Ito, S. TL 1993, 34, 1639.
36. Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. CL 1991, 537.
37. Eguchi, S.; Yamashita, K.; Matsushita, Y. SL 1992, 4, 295.

Steven T. Diver

University of Wisconsin-Madison, WI, USA



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