Diiodomethane

CH2I2

[75-11-6]  · CH2I2  · Diiodomethane  · (MW 267.84)

(precursor to methylene transfer reagents: in combination with various metals or alkyl metals, generates carbenoids which cyclopropanate alkenes1 or methylenate carbonyls;2 precursor to ICH2Met and I2CHMet nucleophiles;3 participates in radical-mediated couplings4)

Alternate Name: methylene iodide.

Physical Data: mp 6 °C; bp 181 °C; d 3.325 g cm-3.

Solubility: slightly sol H2O; sol Et2O, CHCl3, EtOH, hexane, etc.

Form Supplied in: pale yellow liquid; crystallizes as pale yellow needles or plates; typically stabilized with copper powder.

Purification: fractional distillation from CaH2 generally provides reagent of sufficient purity for typical uses.

Handling, Storage, and Precautions: store over copper powder to inhibit radical-induced decomposition; protect from light; incompatible with many metals (Al, Mg, Na, etc.) and strong bases; mildly corrosive; toxicity presumed to be on par with CH2Cl2, i.e. moderately toxic, mutagenic; use in a fume hood.

Methylenations.

A wide variety of carbonyl methylenating reagents utilize CH2I2 as the carbon source. Several of these have proven to be useful alternatives to the Wittig reaction.5 Cainelli and co-workers found that treatment of CH2I2 with 2 equiv of Magnesium Amalgam in the presence of ketones affords alkenes in good yields (eq 1).6 The intermediate in these reactions is presumed to be CH2(MgI)2, and the reaction works well with ketones and aldehydes of variable structure. This reagent is particularly useful for the formation of dideuterated terminal alkenes (using CD2I2, eq 2),7 since methylenation using deuterated Wittig reagents is often accompanied by various degrees of scrambling of the deuterium label.8

Chromium(II) also mediates the alkenation of aldehydes by geminal diiodides (eq 3).9 This transformation presumably proceeds via a 1,1-bis[chromium(III)] species, and works best with substituted diiodides. Generally, high levels of (E) selectivity are obtained.

Certain methylenating reagents utilize CH2I2 in combination with 2 equiv of Zinc and a Lewis acid.2,10,11 A Lewis acid is not essential for this transformation,11 but greatly accelerates the reaction and improves selectivity and yields. The most commonly used Lewis acids include Trimethylaluminum,2,10a Titanium Tetraisopropoxide,10a Titanium(IV) Chloride,10b,10c Dichlorobis(cyclopentadienyl)zirconium,10d and Dichlorobis(cyclopentadienyl)titanium.10e Of a variety of Lewis acids and dihalomethanes examined, Takai and co-workers found that CH2I2/Zn/Me3Al and CH2Br2/Zn/TiCl4 afforded the best results.10f Substrates for these reactions can vary from simple ketones such as acetophenone (eq 4)2 to complex steroidal ketones.10b Chemoselective methylenation of an aldehyde in the presence of a ketone can also be achieved (eq 5).10a Other unsaturated functionalities also react with these reagents. For example, the Eisch reagent10e [CH2(ZnI)2/Cp2TiCl2] has been shown to react with benzonitrile to afford, after hydrolysis, acetophenone (eq 6).

Cyclopropanations.

A variety of metallic species mediate the cyclopropanation of alkenes in the presence of CH2I2 (vide infra). A much simpler procedure is the photolysis of CH2I2 in the presence of alkenes.12 Although this method was initially reported to give a mixture of products in poor yields,12a the addition of iodine scavengers and acid scavengers to the reaction medium results in clean, high-yielding reactions.12b-d Sterically hindered alkanes are cyclopropanated much more readily than with metal-based reagents (eq 7), and double bond geometry is generally retained (eq 8). Remarkably, products arising from C-H bond insertion are not observed, ruling out the formation of free carbene in these reactions. The iodomethyl cation (ICH2+) has been proposed as an intermediate in these reactions.12c,12d

Perhaps the most common use of CH2I2 in organic synthesis is in metal-mediated cyclopropanations. Foremost among these are zinc-mediated cyclopropanations (Simmons-Smith reaction).1,13 This is a widely utilized and versatile transformation. Treatment of CH2I2 and an alkene with Zinc/Copper Couple in refluxing Et2O affords the corresponding cyclopropane, generally in good yield (eq 9).14 The source of the zinc is crucial to the success of the reaction, and several reliable protocols exist.15 The use of Diethylzinc place of the Zn/Cu couple generates a similar reagent;16 this modification has several advantages, including the option of using noncoordinating solvents. In many cases, the use of Chloroiodomethane/Et2Zn in place of CH2I2/Et2Zn is desirable, as the former is more reactive.17 Regardless of the method of reagent generation, the stereochemical course of the reaction is strongly influenced by proximal oxygen substituents (eq 10), and several effective chiral auxiliaries have been developed.18

Similarly, treatment of CH2I2 with a trialkylaluminum reagent (e.g. Triisobutylaluminum) in the presence of alkenes also affords cyclopropanes.19 This reagent system exhibits a reactivity pattern complementary to the zinc- and samarium-based systems, reacting preferentially with isolated alkenes rather than with allylic alcohols (eq 11).19a

A very versatile reagent for the cyclopropanation of alkenes is derived from CH2I2 and Sm(Hg) or Samarium(II) Iodide.20 These reagents react well with allylic alcohols (eq 12)20a,b and enolates (eq 13),20d and are subject to the same hydroxy-directing effects20a,b,f,g as the zinc-based reagents (vide supra). In fact, an oxygen substituent is required for cyclopropanation to occur.20b A diastereoselective cyclopropanation utilizing a chiral acetal as a chiral auxiliary has also recently been reported (eq 14).20g The substitution of ClCH2I for CH2I2 in these reactions often results in higher yields.20b Interestingly, a comparison of the response of the CH2I2/Sm(Hg) and CH2I2/SmI2 reagents towards various allylic alcohols showed little or no difference in either reactivity, chemoselectivity, or stereoselectivity.20b

Nucleophilic Additions of ICH2.

Halomethyllithium reagents are generally unstable except at very low temperatures (<-90 °C),21 but the use of additives such as Lithium Bromide results in greater stability, particularly for Chloromethyllithium and Bromomethyllithium.21c,22 The utility of ICH2Li is still limited, however.23 Fortunately, an alternative method for the generation of an iodomethyl nucleophile has been developed which utilizes Samarium(0) as the metal.3,20c Aldehydes, ketones, and enones all participate well in this reaction, and yields range from moderate to excellent (eq 15). In the illustrated example, the alkene is not cyclopropanated, consistent with the observation that tertiary allylic alcohols react sluggishly with samarium carbenoids.20b

The replacement of an allylic alcohol oxygen by CH2I has also been achieved by the use of aluminum reagents.24 The combination of Triethylaluminum, Et2AlCl, and Et2AlOEt mediates this reaction (eq 16).

Nucleophilic Additions of I2CH.

Deprotonation of CH2I2 by base affords I2CHMet derivatives which are more stable than the corresponding ICH2Met species and react well with a variety of electrophiles.25 Among the bases used successfully are Cy2NLi,25a Sodium Hexamethyldisilazide (NaHMDS),25b Lithium Hexamethyldisilazide (LiHMDS),25b and Lithium Diisopropylamide (LDA).25c I2CHLi reacts well with aldehydes (eq 17),25a and also with silacyclobutanes, affording 2-iodosilacyclopentanes after ring enlargement of the intermediate five-coordinate siliconate (eq 18).25c I2CHNa has been shown to react with electrophiles such as Chlorotrimethylsilane, Ethyl Iodide, and Allyl Iodide.25b

A convenient synthesis of vinyl iodides using I2CHLi has been reported by Julia and co-workers.25b Treatment of CH2I2 with LiHMDS followed by the addition of a lithiated sulfone affords vinyl iodides after aqueous workup. The selectivity is generally low, however (eq 19).

Radical Additions Utilizing CH2I2.

The radical addition of the ICH2 fragment to a,b-unsaturated ketones mediated by Triethylborane provides a route to g-iodo ketones (eq 20).4 The intermediate boron enolates can be either hydrolyzed or alkylated in some cases.4 Vinylsilacyclobutanes are also alkylated by the putative ICH2 radical, affording highly functionalized silylcyclobutane derivatives (eq 21).26

Alkylation Reactions.

CH2I2 has seen limited use as an alkylating reagent, since heterodihalomethanes such as ClCH2I and ClCH2Br are preferred for these reactions.27,28 CH2I2 has been used for alkylative cyclizations, however. A recent interesting application is the formation of 2-imino-1,3-dithiazetidines from thioureas (eq 22).29a Mixtures of isomers are obtained unless one of the urea nitrogen atoms is deactivated as a sulfonamide, amide, or carbamate. In addition, diamines are known to react with CH2I2: slow addition of the diamine to a solution of CH2I2 is necessary to obtain good yields (eq 23).29b

In a mechanistically distinct but related example, dithianes are produced by the Pt-catalyzed coupling of CH2I2 with thiols (eq 24).30

Other Uses.

Several other transformations also utilize CH2I2. For example, heating CH2I2 with 2 equiv of Tin(II) Bromide and a catalytic amount of Triethylamine affords a di-tin compound31a which can be exhaustively methylated to afford bis(trimethylstannyl)methane (eq 25).31b In addition, a convenient procedure for the in situ preparation of the valuable reagent SmI2 involves simply treating Sm powder with CH2I2 in THF.32

Related Reagents.

Chloroiodomethane; Dibromomethane; 1,1-Diiodoethane; Diiodomethane-Zinc-Titanium(IV) Chloride; Iodomethylzinc Iodide.


1. Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M. OR 1972, 20, 1.
2. Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. TL 1978, 2417.
3. (a) Imamoto, T.; Hatajima, T.; Takiyama, N.; Takeyama, T.; Kamiya, Y.; Yoshizawa, T. JCS(P1) 1991, 3127. (b) Tabuchi, T.; Inanaga, J.; Yamaguchi, M. TL 1986, 27, 3891.
4. Nozaki, K.; Oshima, K.; Utimoto, K. BCJ 1991, 64, 403.
5. Maercker, A. OR 1965, 14, 270.
6. Cainelli, G.; Bertini, F.; Grasselli, P.; Zubiani, G. TL 1967, 5153.
7. (a) Hasselman, D. CB 1974, 107, 3486. (b) Hoffman, R. W.; Riemann, A.; Mayer, B. CB 1985, 118, 2493.
8. Atkinson, J. G.; Fisher, M. H.; Horley, D.; Morse, A. T.; Stuart, R. S.; Synnes, E. CJC 1965, 43, 1614.
9. Okazoe, T.; Takai, K.; Utimoto, K. JACS 1987, 109, 951.
10. (a) Okazoe, T.; Hibino, J.-i.; Takai, K.; Nozaki, H. TL 1985, 26, 5581. (b) Lombardo, L. TL 1982, 23, 4293. (c) Hibino, J.-i.; Okazoe, T.; Takai, K.; Nozaki, H. TL 1985, 26, 5579. (d) Tour, J. M.; Bedworth, P. V.; Wu, R. TL 1989, 30, 3927. (e) Eisch, J. J.; Piotrowski, A. TL 1983, 24, 2043. (f) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. BCJ 1980, 53, 1698.
11. See, for example: (a) Miyano, S.; Hida, M.; Hashimoto, H. JOM 1968, 12, 263. (b) Turnbull, P.; Syhora, K.; Fried, J. H. JACS 1966, 88, 4764.
12. (a) Blomstrom, D. C.; Herbig, K.; Simmons, H. E. JOC 1965, 30, 959. (b) Pienta, N. J.; Kropp, P. J. JACS 1978, 100, 655. (c) Kropp, P. J.; Pienta, N. J.; Sawyer, J. A.; Polniaszek, R. P. T 1981, 37, 3229. (d) Kropp, P. J. ACR 1984, 17, 131.
13. (a) Simmons, H. E.; Smith, R. D. JACS 1958, 80, 5323. (b) Simmons, H. E.; Smith, R. D. JACS 1959, 81, 4256.
14. Koch, S. D.; Kliss, R. M.; Lopiekes, D. V.; Wineman, R. J. JOC 1961, 26, 3122.
15. (a) Shank, R. S.; Shechter, H. JOC 1959, 24, 1825. (b) LeGoff, E. JOC 1964, 29, 2048. (c) Rawson, R. J.; Harrison, I. T. JOC 1970, 35, 2057. (d) Denis, J. M.; Girard, C.; Conia, J. M. S 1972, 549. (e) Friedrich, E. C.; Lewis, E. J. JOC 1990, 55, 2491.
16. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. TL 1966, 3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. T 1968, 24, 53. (c) Nishimura, J.; Furukawa, J.; Kawabata, N.; Kitayama, M. T 1971, 27, 1799.
17. (a) Denmark, S. E.; Edwards, J. P. JOC 1991, 56, 6974. (b) Miyano, S.; Yamashita, J.; Hashimoto, H. BCJ 1972, 45, 1946.
18. See, for example: (a) Mash, E. A.; Hemperly, S. B. JOC 1990, 55, 2055, and references cited therein. (b) Mori, A.; Arai, I.; Yamamoto, H. T 1986, 42, 6447. (c) Charette, A. B.; Côté, B.; Marcoux, J.-F. JACS 1991, 113, 8166.
19. (a) Maruoka, K.; Fukutani, Y.; Yamamoto, H. JOC 1985, 50, 4412. (b) Fleming, I.; Lawrence, N. J.; Sarkar, A. K.; Thomas, A. P. JCS(P1) 1992, 3303. (c) Miller, D. B. TL 1964, 989. See also: (d) Hoberg, H. LA 1966, 695, 1. (e) Hoberg, H. LA 1962, 656, 1.
20. (a) Molander, G. A.; Etter, J. B. JOC 1987, 52, 3942. (b) Molander, G. A.; Harring, L. S. JOC 1989, 54, 3525. (c) Imamoto, T.; Takeyama, T.; Koto, H. TL 1986, 27, 3243. (d) Imamoto, T.; Takiyama, N. TL 1987, 28, 1307. (e) Imamoto, T.; Kamiya, Y.; Hatajima, T.; Takahashi, H. TL 1989, 30, 5149. (f) Lautens, M.; Delanghe, P. H. M. JOC 1992, 57, 798. (g) Kabat, M.; Kiegiel, J.; Cohen, N.; Toth, K.; Wovkulich, P. M.; Uskokovic, M. R. TL 1991, 32, 2343.
21. For a review, see: (a) Köbrich, G. AG(E) 1972, 11, 473. See also: (b) Köbrich, G.; Fischer, R. H. T 1968, 24, 4343. (c) Villieras, J.; Rambaud, M.; Kirschleger, B.; Tarhouni, R. BSF(2) 1985, 837.
22. (a) Tarhouni, R.; Kirschleger, B.; Rambaud, M.; Villieras, J. TL 1984, 25, 835. (b) Barluenga, J.; Pedregal, B.; Concellón, J. M.; Yus, M. TL 1993, 34, 4563, and references cited therein.
23. For a recent use of ICH2Li, see: Ambler, P. W.; Davies, S. G. TL 1988, 29, 6983.
24. Ukaji, Y.; Inomata, K. CL 1992, 2353.
25. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010. (b) Charreau, P.; Julia, M.; Verpeaux, J. N. BSF(2) 1990, 275. (c) Matsumoto, K.; Oshima, K.; Utimoto, K. TL 1990, 31, 6055.
26. Matsumoto, K.; Miura, K.; Oshima, K.; Utimoto, K. TL 1991, 32, 6383.
27. For a recent discussion and references, see: Hanh, R. C. JOC 1988, 53, 1331.
28. For a recent attempt to use CH2I2 as a mono-alkylating reagent, see: Shatzmiller, S.; Lidor, R.; Bahar, E. LA 1991, 381.
29. (a) Ried, W.; Mösinger, O. CB 1978, 111, 143. (b) Okajima, N.; Okada, Y. JHC 1991, 28, 177.
30. Page, P. C. B.; Klair, S. S.; Brown, M. P.; Smith, C. S.; Maginn, S. J.; Mulley, S. T 1992, 48, 5933.
31. (a) Bulten, E. J.; Gruter, H. F. M.; Martens, H. F. JOM 1976, 117, 329. (b) Sato, T.; Kikuchi, T.; Tsujita, H.; Kaetsu, A.; Sootome, N.; Nishida, K.-i.; Tachibana, K.; Murayama, E. T 1991, 47, 3281.
32. (a) Namy, J. L.; Girard, P.; Kagan, H. B.; Caro, P. E. NJC 1981, 5, 479. (b) Molander, G. A.; Kenny, C. JACS 1989, 111, 8236.

James P. Edwards

Ligand Pharmaceuticals, San Diego, CA, USA



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