Hexa-m-hydrohexakis(triphenylphosphine)hexacopper1

[(Ph3P)CuH]6

[33636-93-0]  · C108H96Cu6P6  · Hexa-m-hydrohexakis(triphenylphosphine)hexacopper  · (MW 1961.16)

(chemo- and stereoselective conjugate reduction;2,3 catalytic, hydride-mediated, reduction of enones and ketones;4 reduction of alkynes and propargyl alcohols to cis-alkenes5)

Alternate Name: triphenylphosphine copper hydride hexamer.

Physical Data: mp 111 °C (dec).1b

Solubility: sol benzene, toluene, THF (~1 g/10 mL); reacts with CH2Cl2 and CHCl3.

Form Supplied in: bright red crystals to dark red powders; commercially available.

Analysis of Reagent Purity: assay by means of hydrogen evolution.1b 1H NMR spectroscopy (deaerated benzene-d6) shows ligated and, if present, free Ph3P.

Preparative Method: prepared by hydrogenolysis of Ph3P-stabilized Copper(I) t-Butoxide,1c,d which can be generated in situ from t-BuONa and Copper(I) Chloride.1e

Purification: Ph3P is removed by recrystallization from benzene layered with hexanes or acetonitrile under anaerobic conditions, or by trituration with deaerated hexanes or acetonitrile.1e

Handling, Storage, and Precautions: has an indefinite shelf life if stored under an inert atmosphere; can be handled briefly in the air without harm and is stable toward water. The reagent is highly air sensitive in solution; thus only rigorously deoxygenated solvents should be used. For bench top manipulation, transfer of the bulk reagent to a Schlenk tube that can be easily opened under a purge of inert gas and evacuated and backfilled after each use is recommended.

Stoichiometric Reductions.

[(Ph3P)CuH]6 provides stoichiometric conjugate reduction of a,b-unsaturated ketones,2,3 esters,2a,3a aldehydes,2c nitriles,6a sulfones, and sulfonates.3b The reagent is highly chemoselective. Isolated alkenes, carbonyl groups, halogens, and typical oxygenated functionality are not reduced under the reaction conditions (eq 1).2,3

When reducing substrates that are prone to aldol and Michael type reactions, it is advisable to include 5-20 equiv deaerated water in the reaction medium to hydrolyze the intermediate copper enolate. However, reductions run in wet solvents or in the presence of a chlorotrialkylsilane require a slight excess of the reagent to completely consume starting material (0.18-0.5 equiv [(Ph3P)CuH]6).2,3

Initial 1,2-reduction is not competitive and further reaction of the carbonyl product resulting from conjugate reduction is generally only observed with enals. Over-reduction is prevented by running the reactions in the presence of a chlorotrialkylsilane (eq 2).2c Both ketone and aldehyde enolates are thus trapped as their corresponding silyl enol ethers. Alternatively, in the presence of water and excess hydride, some enals can be completely reduced to the saturated alcohol.2c

Stoichiometric reductions are performed at rt in wet deaerated benzene or THF at or below the solubility limit of the reagent. Starting material may remain during reduction of sterically demanding substrates, especially at higher dilution (eq 3).6b Performing such reductions as concentrated suspensions and/or by adding the reagent dropwise to a heated solution of the substrate can help alleviate this difficulty as well as shorten the reaction time.

Aside from offering broad chemoselectivity and complete regioselectivity, the reagent is highly stereoselective, delivering hydride to the less hindered face of the substrate (eqs 3 and 4).2a,b,3 The selectivity exhibited towards 3,5-dimethylcyclohexanone (eq 4) is superior to that observed using either Boeckmans' hydridocuprate (9:1)7a or catalytic hydrogenation (15:1).2a The cis selectivity obtained when reducing tetra- and hexahydronaphthalen-6(7H)-ones (eq 3) parallels that observed with catalytic hydrogenation8 and exceeds the selectivity observed when similar substrates are reduced with hydridocuprate reagents.7 High selectivity for the cis A/B ring juncture is also observed when reducing 3-keto-D4,5 steroidal enones.6b,9

[(Ph3PCuH]6 is also compatible with g-heteroatom-substituted enones (eqs 5 and 6).2b Conjugate reduction of such compounds without elimination of the g-substituent is significant as they can suffer hydrogenolysis during catalytic hydrogenation10 or elimination during reductions where electron transfer is mechanistically relevant.11

Conjugate reduction of b-heteroatom substituted enones is not straightforward.12 However, endocyclic vinylogous esters6b and amides3c react under chlorotrialkylsilane-mediated conditions (eq 7) suggesting that they are reduced through the oxonium and iminium ion, respectively. All efforts to reduce exocyclic vinylogous esters and amides such as 3-substituted cyclohex-2-en-1-ones were unsuccessful.6b

The workup requires exposure of the reaction to air and dilution with ether and/or hexanes. Addition of a small amount of silica gel facilitates decomposition of the copper containing byproducts. After being stirred under air for at least 1 h, the mixture is filtered through silica gel and purified by column chromatography. Alternatively, free Ph3P can be removed from products of similar polarity by oxidation with 5% NaOCl. The resulting phosphine oxide is then removed by simple silica gel filtration. Isolation of the silyl enol ethers requires exposure of the reaction to air and dilution as outlined above, with the usual precautions taken when chromatographing these compounds.

Hydrometalation of Alkynes.

[(Ph3P)CuH]6 reduces alkynes (eq 8) and propargyl alcohols (eq 9) to the cis-alkene.5 Complications include overreduction (<=10%) with some substrates and partial fragmentation of unprotected secondary and tertiary propargyl alcohols. As with enone reductions mediated by [(Ph3P)CuH]6, alkyne reduction is concentration dependent, can be promoted by using higher temperatures, and benefits from the presence of water in the reaction medium.

Catalytic Reductions.

The presumed copper(I) enolate formed during conjugate reduction heterolytically activates H2, allowing the reductions to proceed catalytically in copper.4 In the presence of excess Ph3P (4-6 equiv per Cu) and H2 pressure (200-1000 psi) the catalytic enone reduction can be reasonably controlled, providing either conjugate reduction or complete reduction to saturated alcohol, depending on reaction conditions.4 While work to provide a synthetically useful catalytic enone reduction continues, a practical catalytic reduction of ketones under one atmosphere of H2 has been developed (eq 10).6b The catalytic reducing system is prepared simply by adding Me2PPh (6-10 equiv per Cu) to [(Ph3P)CuH]6 followed by t-BuOH (10-20 equiv per Cu) and the reducible substrate (10-100 equiv per Cu) in dry, deaerated benzene (0.4-0.8 M in substrate) under an inert atmosphere. The solution is then subjected to one freeze-pump-thaw-degas cycle and an atmosphere of H2 is admitted as the solution thaws. Alternatively, the catalyst can be prepared by substituting Copper(I) Chloride and NaO-t-Bu for [(Ph3P)CuH]6. Me2PPh is superior to numerous other tertiary phosphines screened. This catalyst is quite robust, allowing the reactions to be monitored by TLC and displaying sustained turnover, as indicated by reduction of fresh substrate added to a completed reaction. The chemoselectivity is comparable to that of [(Ph3P)CuH]6 with the exception that this catalyst does reduce ketones effectively but reacts with enones to give mixtures of saturated and allylic alcohols. The reduction of cyclic ketones proceeds mainly by axial delivery of hydride, with stereoselectivity exceeding Sodium Borohydride and Lithium Aluminum Hydride in many cases (eq 11).6b,13

Related Reagents.

Lithium n-Butyl(hydrido)cuprate.


1. (a) Bezman, S. A.; Churchill, M. R.; Osborn, J. A.; Wormald, J. JACS 1971, 93, 2063. (b) Churchill, M. R.; Bezman, S. A.; Osborn, J. A.; Wormald, J. IC 1972, 11, 1818. (c) Goeden, G. V.; Caulton, K. G. JACS 1981, 103, 7354. (d) Lemmen, T. H.; Folting, K.; Huffman, J. C.; Caulton, K. G. JACS 1985, 107, 7774. (e) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker, J. M. TL 1988, 29, 3749.
2. (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. JACS 1988, 110, 291, and references therein. (b) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. TL 1990, 31, 3237. (c) Brestensky, D. M.; Stryker, J. M. TL 1989, 30, 5677.
3. (a) Ziegler, F. E.; Tung, J. S. JOC 1991, 56, 6530. (b) Musicki, B.; Widlanski, T. S. TL 1991, 32, 1267. (c) Meyers, A. I.; Elworthy, T. R. JOC 1992, 57, 4732. (d) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. JACS 1992, 114, 3162. (e) Cai, S.; Stroud, M. R.; Hakomori, S.; Toyokuni, T. JOC 1992, 57, 6693.
4. (a) Mahoney, W. S.; Stryker, J. M. JACS 1989, 111, 8818. (b) Stryker, J. M.; Mahoney, W. S.; Brestensky, D. M.; Daeuble J. F. In Catalysis of Organic Reactions; Pascoe, W. E., Ed.; Dekker: New York, 1992; Vol. 47, pp 29-44. (c) Mahoney, W. S., Ph.D. Dissertation, Indiana University, 1989.
5. (a) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. TL 1990, 31, 2397, and references therein.
6. (a) Brestensky, D. M., Ph.D. Dissertation, Indiana University, 1992. (b) Daeuble, J. F., Ph.D. Dissertation, Indiana University, 1993.
7. (a) Boeckman, R. K., Jr.; Michalak, R. JACS 1974, 96, 1623. (b) Review detailing reactivity of other hydridocuprates: Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135.
8. House, H. O. Modern Synthetic Reactions; Benjamin: Menlo Park, CA, 1972.
9. Hydrogenation of 3-keto-D4,5 steroidal enones over Cu0/Al2O3 also gives the cis A/B ring juncture, but with lower selectivity: Ravasio, N.; Rossi, M. JOC 1991, 56, 4329.
10. (a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis; Academic: New York, 1979; pp 235-250. (b) Rylander, P. N. Hydrogenation Methods; Academic: London, 1985; pp 148-183.
11. (a) Ruden, R. A.; Litterer, W. E.; TL 1975, 2043. (b) Smith, R. A. J.; Hannah, D. J. T 1979, 35, 1183. (c) Nilsson, A.; Ronlá, A. TL 1975, 16, 1107. (d) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. JACS 1965, 87, 275. (e) A recently reported hydridocuprate is also compatible with g-hetero substituted enones: Lipshutz, B. H.; Ung, C. S.; Sengupta, S. SL 1989, 64.
12. (a) Posner, G. H.; Brunelle, D. J. CC 1973, 907. (b) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. TL 1986, 27, 4029. (c) House, H. O.; Umen, M. J. JOC 1973, 38, 3893.
13. The octahydronaphthalen-6(7H)-one (eq 9) is reduced by NaBH4 with the same facial selectivity for the equatorial alcohol (9:1): Lin, Y. Y.; Jones, J. B. JOC 1973, 38, 3575.

John F. Daeuble

Indiana University, Bloomington, IN, USA

Jeffrey M. Stryker

University of Alberta, Edmonton, Alberta, Canada



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