Copper(I) Oxide


[1317-39-1]  · Cu2O  · Copper(I) Oxide  · (MW 143.08)

(weak base; activates halides towards nucleophilic substitution;1 forms carbenoid intermediates from diazo compounds2 and radicals from arenediazonium salts;3 activates isocyanides towards 1,1-addition4)

Physical Data: mp 1235 °C; d ~6 g cm-3.

Solubility: insol most organic solvents; slightly sol quinoline and benzonitrile;1a variously sol acids (salt formation, in some cases disproportionation to Cu0 and CuII).

Form Supplied in: red to brown powder; widely available. Typical impurities: Cu, CuO,5 NaCl,5 stabilizers (e.g. gelatine,5 oil, zinc stearate), moisture.5 For reactions in anhydrous media the reagent is vacuum-dried before use.

Preparative Methods: since reactions involving Cu2O are heterogeneous, they may critically depend on the particle size.6b An active preparation is obtained by reduction of CuII solutions7 but may suffer deactivation at high reaction temperatures.1a

Handling, Storage, and Precautions: Cu2O is incompatible with alkynes, diazonium salts, and diazo compounds. Copper compounds are moderately toxic.

Activation of Halides Towards Nucleophilic Substitution.

Aryl halides react in the presence of Cu2O with a variety of nucleophiles such as thiols and thiolates (eq 1),6 phenols and phenoxides (eq 1),1a,8,9 ammonia and amines,9,10 lactams (eq 2),11 cyclic imides,11,12 Sodium Borohydride,5 and alkynes (eq 3).13 Copper thiolates have been prepared from Cu2O and subsequently used in a separate step.6a,b Lithium Bromide or Tetra-n-butylammonium Bromide transforms iodides into bromides.1a Typical solvents include pyridine, 2,4,6-collidine, quinoline, DMF, and DMA; elevated temperatures are required. DMSO has been used but methylthiolation occurs as a side reaction.1a The order of reactivity is chlorides < bromides < iodides. Besides aryl halides, vinyl halides and also 1-bromododecane react with CuSPh in good yields.6a An allylic iodide has been hydrolyzed by warming with Cu2O in DMSO/water.14 Fluorides are obtained from secondary and tertiary aliphatic chlorides or bromides with Hydrogen Fluoride and Cu2O in ether or THF.15

Reduction is a common side reaction for aryl halides,1,5,9,10e especially with alkoxides and with phenols bearing electron-withdrawing substituents. With Sodium Ethoxide in refluxing 2,4,6-collidine, reduction can be the main pathway.5 The same reagent system reduces a-bromo ketones to ketones.5,10e Replacement of Cu2O by Copper(I) Iodide gives largely substitution for sodium derivatives of n-alkanols and cyclohexanol.16 Reduction of 1-bromonaphthalene also predominates with carboxylic acids,17 whereas haloferrocenes give acyloxyferrocenes.18 Ullmann coupling to form biaryls is occasionally observed.1,19

Thiophenes,20 benzothiazole,21 pentafluorobenzene (eq 4),20 and di- and trinitrobenzenes22 are arylated by aryl iodides/Cu2O. Carboxylic acids may also serve as starting materials, the reaction then proceeding with concomitant decarboxylation (see below).23


Aromatic and vinylic carboxylic acids are decarboxylated by heating with Cu2O (alone or with addition of 2,2-bipyridyl)24 in high-boiling solvents such as DMF, NMP, or quinoline. The Cu2O-bipyridyl protocol has been applied to a homocubanecarboxylic acid which decarboxylates with skeletal rearrangement.25 On dry heating with Cu2O, a-cyanoacrylic acids furnish predominantly cis-a,b-unsaturated nitriles (eq 5).26 Malonic acids (eq 6)27 as well as some arylacetic acids capable of forming stabilized benzylic anions28 decarboxylate with Cu2O in acetonitrile.

Vicinal dicarboxylic acids undergo oxidative bisdecarboxylation to form alkenes when treated with Cu2O and 2,2-bipyridyl (eq 7).29 Yields are usually higher than those obtained by electrolysis or with Lead(IV) Acetate but aromatization may interfere. Under 1 bar of oxygen at 50 °C, diphenylacetic acid and a-hydroxy carboxylic acids are oxidatively decarboxylated to ketones by Cu2O in acetonitrile.30

Reactions of Diazo Compounds.

Cu2O acts as a catalyst for the decomposition of a-diazo carbonyl compounds (more often used are Copper powder or Copper(II) Sulfate) to give rise, via carbenoid intermediates, to cyclopropanation (eq 8) and C-H insertion (eq 9) products.2 Most examples are intramolecular, but the reaction of N-methylpyrrole with ethyl diazoacetate giving predominantly insertion into the a-C-H bond has been described.31 The performance of Cu2O vs. other catalysts is variable.2 In the intramolecular cyclopropanation of a 4-diazoindol-7-one derivative, a copper(I) triflate carbonyl complex prepared in situ from Cu2O gave best results.32

Reactions of Diazonium Salts.

Copper(I) oxide forms radicals from arenediazonium salts which may undergo subsequent transformations like reduction (eq 10),33 coupling to form biaryls,34 oxidation to phenols by copper(II) nitrate (eq 11),3 Meerwein arylation of acrylic acid derivatives,35 homolytic aromatic substitution (eq 12),3,36 or substitution by nitrite.37 The oxidation reaction offers the advantage to uncatalyzed thermolysis in that it proceeds without heating or a large excess of strong acid and usually gives phenols, even in cases where cyclization onto an ortho substituent normally predominates.

1,1-Addition to Isocyanides.

Substituted formimidates are obtained from isocyanides and alcohols, thiols, amines (eq 13), or amides in the presence of Cu2O.4 The intramolecular version of this reaction, combined in one pot with the hydroxyalkylation of an activated (allyl, benzyl, a-alkoxycarbonyl) isocyanide by an aldehyde or ketone, results in D2-oxazolines.38 Selenol esters as electrophiles yield oxazoles (eq 14),39 and a,b-unsaturated esters or nitriles produce D1-pyrrolines.38 Analogous schemes involving aromatic side chain metalation have been utilized in the synthesis of indoles (eq 15),40 3,1-benzoxazepines,41 3,1-benzoxazocines,41 and 1,3-benzodiazepin-4-ones.40a

Miscellaneous Reactions.

Cu2O catalyzes a variety of other transformations such as the Koch carboxylation of alkenes and alcohols by CO in strong acids. The reaction proceeds via carbenium ions, and skeletal rearrangements are the rule.42 Polyhalomethanes and di- and trichloroacetic acid esters add to 1,3-butadiene and styrene.43 Terminal alkynes form dimeric vinyl alkynes in boiling AcOH (eq 16).44 Michael additions are catalyzed by Cu2O in the presence of isocyanides,45 as is the esterification of carboxylic acids with alkyl halides46 and the cyclopropanation of electron-poor alkenes with a-halo carbonyl and trichloromethyl compounds.38c,47 Exclusive b-hydrosilylation of acrylonitrile occurs with Cu2O and TMEDA under sonication.48 Cyclohexene is acetoxylated in up to 30% enantiomeric excess by t-Butyl Hydroperoxide and AcOH in acetonitrile with Cu2O/proline as catalyst.49 Autoxidation of furfural to furoic acid takes place in the presence of a Cu2O-Ag2O catalyst.50 Allylic alcohols are transformed into acetates with oxygen attached to the less substituted terminus by Cu2O in AcOH/Ac2O (eq 17).51 Copper(II) Trifluoromethanesulfonate in the presence of Cu2O in nitrile solvents oxidatively couples enol silyl ethers to 1,4-diketones52 and oxidatively cyclizes d,ε- and ε,ζ-unsaturated enol silyl ethers (eq 18).53

Related Reagents.

For related chemistry, see the entries dealing with other copper(I) and copper(II) reagents.

1. (a) Bacon, R. G. R.; Hill, H. A. O. JCS 1964, 1108. (b) Bacon, R. G. R.; Hill, H. A. O. QR 1965, 19, 95.
2. Burke, S. D.; Grieco, P. A. OR 1979, 26, 361.
3. Cohen, T.; Dietz, A. G., Jr.; Miser, J. R. JOC 1977, 42, 2053.
4. Saegusa, T.; Murase, I.; Ito, Y. JOC 1971, 36, 2876.
5. Bacon, R. G. R.; Rennison, S. C. JCS(C) 1969, 308.
6. (a) Adams, R.; Ferretti, A. JACS 1959, 81, 4927. (b) Adams, R.; Reifschneider, W.; Ferretti, A. OSC 1973, 5, 107. (c) Jones, E.; Moodie, I. M. OSC 1988, 6, 558. (d) De Jong, F.; Janssen, M. J. JOC 1971, 36, 1998. (e) Ashby, J.; Ayad, M.; Meth-Cohn, O. JCS(P1) 1973, 1104. (f) Janssen, M. J.; Bos, J. AG(E) 1969, 8, 598.
7. for example: (a) King, A. Inorganic Preparations, rev. ed.; Allen & Unwin: London, 1950; p 40. (b) Weygand, C. Organic Preparations; Interscience: New York, 1945; p 296.
8. Crowder, J. R.; Glover, E. E.; Grundon, M. F.; Kaempfen, H. X. JCS 1963, 4578.
9. Bacon, R. G. R.; Stewart, O. J. JCS 1965, 4953.
10. (a) Doak, G. O.; Freedman, L. D. JACS 1953, 75, 683. (b) Freedman, L. D.; Doak, G. O. JOC 1964, 29, 2450. (c) Pews, R. G.; Gall, J. A. JFC 1991, 53, 307. (d) Bacon, R. G. R.; Maitland, D. J. JCS(C) 1970, 1973. (e) Bacon, R. G. R.; Stewart, O. J. JCS(C) 1969, 301.
11. Yamamoto, T.; Kurata, Y. CJC 1983, 61, 86.
12. Sato, M.; Ebine, S.; Akabori, S. S 1981, 472.
13. Doad, G. J. S.; Barltrop, J. A.; Petty, C. M.; Owen, T. C. TL 1989, 30, 1597.
14. Yoshioka, M. et al. TL 1980, 21, 351.
15. Yoneda, N.; Fukuhara, T.; Nagata, S.; Suzuki, A. CL 1985, 1693.
16. Bacon, R. G. R.; Rennison, S. C. JCS(C) 1969, 312.
17. Bacon, R. G. R.; Hill, H. A. O. JCS 1964, 1112.
18. Sato, M.; Lam, Y. P.; Motoyama, I.; Hata, K. BCJ 1971, 44, 808.
19. (a) Bacon, R. G. R.; Pande, S. G. JCS(C) 1970, 1967. (b) Cava, M. P.; Stucker, J. F. JACS 1955, 77, 6022.
20. (a) Ljusberg, H.; Wahren, R. ACS 1973, 27, 2717. (b) Nilsson, M. TL 1966, 679.
21. Chodowska-Palicka, J.; Nilsson, M. S 1974, 128.
22. (a) Björklund, C.; Nilsson, M. TL 1966, 675. (b) ACS 1968, 22, 2338. (c) ACS 1968, 22, 2581. (d) Björklund, C.; Nilsson, M.; Wennerström, O. ACS 1970, 24, 3599.
23. (a) Nilsson, M. ACS 1966, 20, 423. (b) Björklund, C.; Nilsson, M. ACS 1968, 22, 2585. (c) Nilsson, M.; Ullenius, C. ACS 1968, 22, 1998. (d) Cairncross, A.; Roland, J. R.; Henderson, R. M.; Sheppard, W. A. JACS 1970, 92, 3187.
24. Cohen, T.; Schambach, R. A. JACS 1970, 92, 3189.
25. Dauben, W. G.; Twieg, R. J. TL 1974, 531.
26. Fairhurst, J.; Horwell, D. C.; Timms, G. H. TL 1975, 3843.
27. (a) Toussaint, O.; Capdevielle, P.; Maumy, M. S 1986, 1029. (b) Larchevêque, M.; Petit, Y. S 1991, 162.
28. Toussaint, O.; Capdevielle, P.; Maumy, M. T 1984, 40, 3229.
29. Snow, R. A.; Degenhardt, C. R.; Paquette, L. A. TL 1976, 4447.
30. Toussaint, O.; Capdevielle, P.; Maumy, M. TL 1984, 25, 3819.
31. Maryanoff, B. E. JHC 1977, 14, 177.
32. Sundberg, R. J.; Pitts, W. J. JOC 1991, 56, 3048.
33. (a) Review: Kornblum, N. OR 1944, 2, 262. (b) Hodgson, H. H.; Turner, H. S. JCS 1943, 86. (c) Finger, G. C.; White, R. H. JOC 1958, 23, 1612. (d) Korzeniowski, S. H.; Blum, L.; Gokel, G. W. JOC 1977, 42, 1469.
34. (a) Atkinson, E. R.; Lawler, H. J. JACS 1940, 62, 1704. (b) Atkinson, E. R.; Lawler, H. J.; Heath, J. C.; Kimball, E. H.; Read, E. R. JACS 1941, 63, 730. (c) Atkinson, E. R.; Morgan, C. R.; Warren, H. H.; Manning, T. J. JACS 1945, 67, 1513.
35. (a) Oyama, K.; Haradam, T. CA 1985, 103, 141 641s. (b) Davidson, R. I. CA 1986, 105, 174 806u.
36. (a) McKenzie, T. C.; Epstein, J. W. JOC 1982, 47, 4881. (b) Matsuda, A.; Satoh, K.; Tanaka, H.; Miyasaka, T. S 1984, 963.
37. (a) Sandmeyer, T. CB 1887, 20, 1494. (b) Hodgson, H. H.; Marsden, E. JCS 1944, 22.
38. (a) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. JOC 1971, 36, 3316. (b) Saegusa, T.; Murase, I.; Ito, Y. BCJ 1972, 45, 830. (c) Review: Saegusa, T.; Ito, Y. S 1975, 291.
39. Kozikowski, A. P.; Ames, A. JACS 1980, 102, 860.
40. (a) Ito, Y.; Kobayashi, K.; Saegusa, T. TL 1979, 1039. (b) JACS 1977, 99, 3532. (c) JOC 1979, 44, 2030. (d) Ito, Y.; Inubushi, Y.; Sugaya, T.; Kobayashi, K.; Saegusa, T. BCJ 1978, 51, 1186.
41. Ito, Y.; Kobayashi, K.; Saegusa, T. TL 1978, 2087.
42. (a) Souma, Y.; Sano, H.; Iyoda, J. JOC 1973, 38, 2016. (b) Yoneda, N.; Fukuhara, T.; Takahashi, Y.; Suzuki, A. BCJ 1978, 51, 2347.
43. (a) Vít, Z.; Hájek, M. CCC 1987, 52, 1280. (b) Hájek, M.; Hetflejsova, B. CA 1988, 109, 189 975e.
44. Garwood, R. F.; Oskay, E.; Weedon, B. C. L. CI(L) 1962, 1684.
45. Saegusa, T.; Ito, Y.; Tomita, S.; Kinoshita, H. BCJ 1972, 45, 496.
46. Saegusa, T.; Murase, I.; Ito, Y. JOC 1973, 38, 1753.
47. (a) Saegusa, T.; Ito, Y.; Yonezawa, K.; Inubushi, Y.; Tomita, S. JACS 1971, 93, 4049. (b) Saegusa, T.; Yonezawa, K.; Ito, Y. SC 1972, 2, 431.
48. Rajkumar, A. B.; Boudjouk, P. OM 1989, 8, 549.
49. Muzart, J. J. Mol. Catal. 1991, 64, 381.
50. Harrisson, R. J.; Moyle, M. OSC 1963, 4, 493.
51. (a) Miyawaki, H. CA 1979, 91, 157 941j. (b) CA 1981, 95, 169 543b.
52. Kobayashi, Y.; Taguchi, T.; Morikawa, T.; Tokuno, E.; Sekiguchi, S. CPB 1980, 28, 262.
53. Snider, B. B.; Kwon, T. JOC 1992, 57, 2399.

Werner Tückmantel

Mayo Foundation for Medical Education and Research, Jacksonville, FL, USA

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