Sodium Iodide-Copper1

NaI/Cu
(NaI)

[7681-82-5]  · INa  · Sodium Iodide-Copper  · (MW 149.89) (Cu)

[7440-50-8]  · Cu  · Sodium Iodide-Copper  · (MW 63.55)

(mild two-electron reductant, capable of generating weakly electrophilic sodium oxyallyl cations from a,a-dibromo ketones; capture of nucleophilic 1,3-dienes affords seven-membered unsaturated ketones)

Physical Data: NaI: mp 661 °C; bp 1304 °C; d 3.67 g cm-3.

Solubility: NaI: sol water, alcohol, acetone, acetonitrile.

Form Supplied in: NaI: white odorless, deliquescent crystals or granules. Drying: sodium iodide (together with commercially available copper powder) is dried in a flame-dried reaction flask for 3 h at 150 °C under reduced pressure (oil pump).

Handling, Storage, and Precautions: NaI: gradually absorbs up to ca. 5% (0.5 mol) moisture when exposed to air. Slowly becomes brown in air due to liberation of iodine. Keep well closed and protected from light.

Sodium Oxyallyl Intermediates.

Sodium oxyallyl cations, conveniently generated from a,a-dibromo ketones and anhydrous Sodium Iodide in the presence of Copper powder in anhydrous acetonitrile, are weak and selective electrophilic intermediates, which combine with nucleophilic 1,3-dienes to give 4-cycloheptenones. Iodide ion (2 equiv) functions as a two-electron reductant. Molecular iodine liberated during the reaction (eq 1) is removed efficiently by metallic copper powder (eq 2), while the reaction solution assumes a characteristic oatmeal color.1-3

The mode of workup is important, in order to avoid decomposition of sensitive cycloadducts. The reaction mixture is cooled, and remaining copper and sodium salts are suction filtered. Filtration through silica gel is also helpful at this stage. Usually, the acetonitrile mother liquor (which can be concentrated further under reduced pressure at 0 °C) contains dissolved CuHal and is taken up in ice-cooled dichloromethane. The combined organic phase is washed with ice-cold ammonia, until the blue color disappears. (In aqueous solution, CuI disproportionates: 2 CuI -> Cu + CuII; the reaction is driven by complexation of CuII with NH3). Standard workup (evaporation of solvent, chromatography on silica gel, and, in the case of the major a,a-configurated stereoisomer, crystallization) affords the oxa-bridged seven-membered ketone (eq 3).2 Among cyclic dienes, Furan (bp 31 °C) is especially useful, because it can be used in excess without problems, serves as a solvent for the a,a-dibromo ketone, and is removed easily on workup.

In place of furan (eq 3), other cyclic dienes have been reacted with 2,4-Dibromo-3-pentanone (1), including Cyclopentadiene, 6,6-Dimethylfulvene, and 6-acetoxyfulvene.4 These give (2), (3), and (4), respectively; only the major stereoisomer with a,a-configured dimethyl groups is shown. The bicyclic dione (5), the hypothetical adduct of cyclopentadienone, has been prepared by hydrolysis and oxidation of 8-acetoxymethylene-2,4-dimethylbicyclo[3.2.1]oct-6-en-3-one (4) (eq 4)4 (the minor stereoisomer is a,b-configurated in this case).

a-Alkylated 2,6-dibromocyclohexanones and NaI/Cu also enter into reductive intermolecular cyclodehalogenation, giving unsaturated tricyclic ketones.5,6 The preparation of 1-isopropyl-7-methyl-11-oxatricyclo[4.3.1.12,5]undec-3-en-10-one (6) from furan and a,a-dibromomenthone has been optimized.6,7

The reaction of dibromo ketones derived from (5R)- and (5S)-menthone affords enantiomerically pure tricyclic compounds (eqs 5 and 6).3

For cycloadditions with Cyclopentadiene, it is advantageous to precool the cyclopentadiene to -78 °C and to add it slowly by syringe to the reaction mixture, synchronously with the a,a-dibromo ketone which is added with another syringe.5 Other tricyclic compounds (7) and (8) have been prepared in similar fashion.5,7,8

The series of cycloadducts (9)-(11) derived from 2,6-dibromo-2,6-dimethylcyclohexanone is of interest, because the ketone is flanked by two quaternary carbon atoms.5,6

Starting from the acyclic ditertiary dibromo ketone (12) and the secondary-tertiary dibromo ketone (13), the furan and cyclopentadiene adducts are accessible in good yield (eqs 7 and 8). In these cases the NaI/Cu procedure is the recommended alternative9 to the Zinc/Copper Couple and the Nonacarbonyldiiron procedures, which have been used more frequently in the past.3,10,11

Pyrroles and alkylated pyrroles afford unsaturated b-amino ketones (14)-(16) (bicyclic Mannich bases) in a simple one-pot procedure.12,13 Temporary tethering of the sodium cation by the ethoxycarbonyl group of the pyrrole is thought to facilitate the formation of the azabicyclic compound (16), which has been obtained in high isolated yield.13 From the point of view of substitution pattern, the oxyallyl cation route to 6,7-dehydrotropinones complements the well-known synthesis of the alkaloid (±)-tropinone (N-methyl-9-azabicyclo[3.2.1]octan-3-one) by Robinson14a and Schöpf.14b,15

Reaction of Isoprene with the isoprenoid primary-tertiary a,a-dibromo ketone (17) affords monoterpenoid ethers on extractive workup. Claisen rearrangement of the major isomer at higher temperature (Ea = 33.6 kcal mol-1) yields 2,2,4-trimethyl-4-cycloheptenone, while the minor ether gives karahanaenone (eq 9).20a The two isomeric seven-membered ketones are obtained directly and more easily from isoprene and more electrophilic isoprenoid metal oxyallyl cation intermediates.3,20b

In summary, NaI/Cu in acetonitrile is a simple and inexpensive reagent that allows the generation of sodium oxyallyl cation intermediates from a number of a,a-dibromo ketones, as exemplified by the disecondary (1), ditertiary (12), and secondary-tertiary (13) dibromo ketones. These intermediates have been trapped with nucleophilic dienes to give seven-membered rings. For structurally and electronically more demanding cycloadditions, other methods for generating allyl cations are required. Frequently, but not necessarily, a preformed allylic halide or ester, with a donor substituent at the central allyl carbon atom, is treated with a Lewis acid in the presence of the diene at low temperature.21-24 In all cases, the electrophilicity of the allyl cation and, equally important, its hidden nucleophilicity (cf. stepwise class B reactions3) must be tailored carefully to match the reactivity of the diene.

Acyl Iodides and Related Derivatives.

Sodium iodide in acetonitrile (in the presence or absence of copper powder) is the reagent of choice for preparing acyl iodides from acyl chlorides (eq 10) A wide variety of acyl chlorides react in excellent yield, including sterically hindered pivaloyl chloride (80%), adamantanecarbonyl chloride (93%), and aromatic derivatives. The reaction is monitored by precipitation of sodium chloride. Acyl iodides are surprisingly lipophilic, due to the large iodine atom, and are isolated by continuous extraction from the mother liquor with pentane, using the low temperature reactor-extractor25 (cf. eq 9). The structure of the acyl iodides is indicated by the diagnostic 13C NMR upfield shift of the iodocarbonyl atom (heavy atom effect).25

Using the same methodology, Hoffmann and his co-workers have also prepared dicarboxylic acid iodides. For example, hexanedioyl diiodide (from the dichloride of adipic acid) has been isolated as heavy, snow-white crystals by extraction into pentane. When exposed to air the compound is oxidized readily, first turning yellow and then brown with simultaneous fuming.26 Under the same conditions, chloroformates have been converted into iodoformic esters.27


1. Ashcroft, M. R.; Hoffmann, H. M. R. OSC 1988, 6, 512. The results shown (eq 3) correspond to scale-up by a factor of 2.5, using 256 mmol of 2,4-dibromo-3-pentanone: Nowakowski, M., unpublished results.
2. The b,b-adduct is the minor isomer (3%) in the NaI/Cu procedure. Using more electrophilic metal oxyallyl cation intermediates, one may increase the yield of this stereoisomer at the expense of the a,a-configured adduct. See Ref. 3, sections 4.2 and 4.3.
3. Hoffmann, H. M. R. AG(E) 1984, 23, 1.
4. Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. R. JACS 1979, 101, 1786.
5. Hoffmann, H. M. R.; Wagner, D.; Wartchow, R. CB 1990, 123, 2131, 2460.
6. Schottelius, T.; Hoffmann, H. M. R. CB 1991, 124, 1673.
7. (a) Beer, T.; Hoffmann, H. M. R. Photochemical Key Steps in Organic Synthesis; Mattay, J.; Griesbeck, A., Eds.; VCH: Weinheim, 1994. (b) Beer, T. Ph.D. Thesis, University of Hannover, 1994.
8. Stohrer, I.; Hoffmann, H. M. R. T 1992, 48, 6021.
9. (a) Stohrer, I. Ph.D. Thesis, University of Hannover, 1992. (b) Stohrer, I.; Hoffmann, H. M. R. HCA 1993, 76, 2194.
10. Noyori, R.; Hayakawa, Y. OR 1983, 29, 163.
11. Mann, J. T 1986, 42, 4611.
12. Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. AG(E) 1974, 13, 410.
13. Dannenberg, C. Ph.D. Thesis, University of Hannover, 1993.
14. Succinic dialdehyde, methylamine, and acetonedicarboxylic acid are condensed in biomimetic fashion: (a) Robinson, R. JCS 1917, 762. (b) Schöpf, C.; Lehmann, G.; Arnold, W. AG 1937, 50, 783.
15. The parent 6,7-dehydrotropinone can be prepared with more electrophilic oxyallyl cation intermediates and an N-acceptor-substituted pyrrole, e.g. N-methoxycarbonylpyrrole.10,16,17 Probably the method of choice for preparing parent [3.2.1]bicyclic ketones (from tetrabromoacetone) is the triethyl borate/zinc procedure.18,19 Monoalkylated derivatives are available by the same procedure.18
16. Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. JACS 1978, 100, 1786.
17. Mann, J.; de Almeida Barbosa, L.-C. JCS(P1) 1992, 787.
18. Hoffmann, H. M. R.; Iqbal, M. N. TL 1975, 4487.
19. Ansell, M. F.; Mason, J. S.; Caton, M. P. L. JCS(P1) 1984, 1061.
20. (a) Chidgey, R.; Hoffmann, H. M. R. TL 1978, 1001. (b) Chidgey, R.; Hoffmann, H. M. R. TL 1977, 2633.
21. For example: (a) Hoffmann, H. M. R.; Matthei, J. CB 1980, 113, 3837. (b) Henning, R.; Hoffmann, H. M. R. TL 1982, 23, 2305. (c) Hoffmann, H. M. R.; Eggert, U.; Gibbels, U.; Giesel, K.; Koch, O.; Lies, R.; Rabe, J. T 1988, 44, 3899.
22. (a) Kaiser, R.; Föhlisch, B. HCA 1990, 73, 1504. (b) Föhlisch, B.; Herter, R. CB 1984, 117, 2580.
23. Giguere, R. J.; Tassely, S. M.; Rose, M. I.; Krishnamurthy, V. V. TL 1990, 31, 4577.
24. Harmata, M.; Elahmad, S. TL 1993, 34, 789.
25. Hoffmann, H. M. R.; Haase, K. S 1981, 715.
26. Hoffmann, H. M. R.; Haase, K.; Geschwinder, P. M. S 1982, 237.
27. Hoffmann, H. M. R.; Iranshahi, L. JOC 1984, 49, 1174.

H. Martin R. Hoffmann

University of Hannover, Germany



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